Showing papers in "International Journal of Oncology in 2022"
TL;DR: A mechanistic study revealed that miR‑181d‑5p directly targeted neurocalcin δ (NCALD) to inhibit the 5‑FU sensitivity of CRC cells, providing novel insight into exosomal microRNAs in 5‐FU sensitivity in CRC cells.
Abstract: Resistance to 5‑Fluorouracil (5‑FU) is a frequent occurrence in patients with colorectal cancer (CRC). MicroRNAs (miRNAs) from cancer‑associated fibroblasts (CAFs)‑secreted exosomes have been associated with 5‑FU sensitivity. The potential molecular mechanism of CAFs‑exosomal miRNAs in CRC remains unclear. The aim of the present study was to elucidate the role of exosomal miRNAs in 5‑FU sensitivity in CRC. Exosomes derived from CAFs were extracted. Exosomal miR‑181d‑5p was identified as a miRNA associated with 5‑FU sensitivity. The putative function of exosomal miR‑181d‑5p was evaluated by ethynyl‑2‑deoxyuridine staining, flow cytometry, RNA immunoprecipitation, luciferase reporter assay, tumor xenograft formation, reverse transcription‑quantitative PCR and western blot analysis. Modification of miR‑181d‑5p by the RNA N6‑methyladenosine (m6A) methyltransferase like (METTL)3 was examined by m6A methylation analysis. The results indicated that m6A modification and METTL3 expression were upregulated in CRC patients. METTL3‑dependent m6A methylation promoted the miR‑181b‑5p process by DiGeorge Syndrome Critical Region 8 (DGCR8) in CAFs. CAFs‑derived exosomes inhibited 5‑FU sensitivity in CRC cells through the METTL3/miR‑181d‑5p axis. A mechanistic study revealed that miR‑181d‑5p directly targeted neurocalcin δ (NCALD) to inhibit the 5‑FU sensitivity of CRC cells. Patients with higher NCALD levels exhibited a higher survival rate. Taken together, METTL3‑dependent m6A methylation was upregulated in CRC to promote the processing of miR‑181d‑5p by DGCR8. This led to increased miR‑181d‑5p expression, which inhibited the 5‑FU sensitivity of CRC cells by targeting NCALD. The results of the present study provided novel insight into exosomal microRNAs in 5‑FU sensitivity in CRC cells. Furthermore, exosomal miR‑181d‑5p may represent a potential prognostic marker for CRC.
31 citations
TL;DR: This paper is retracted on account of a lack of confidence in the presented data and the authors did provide an explanation to account for the duplication of the data, although this was not accepted by the Editorial Board.
Abstract: Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the TUNEL assay data shown in Fig. 6C were strikingly similar to images that had already appeared in Fig. 8B in another article that appeared in the journal Oncotarget [Chen W, Xu X-K, Li J-L, Kong K-K, Li H, Chen C, He J, Wang F, Li P, Ge X-S and Li F-C: MALAT1 is a prognostic factor in glioblastoma multiforme and induces chemoresistance to temozolomide through suppressing miR-203 and promoting thymidylate synthase expression. Oncotarget 8: 22783-22799, 2017]. Owing to the fact that the contentious data in the above article had already been published elsewhere prior to its submission to International Journal of Oncology, the Editor has decided that this paper should be retracted from the Journal on account of a lack of confidence in the presented data. The authors did provide an explanation to account for the duplication of the data, although this was not accepted by the Editorial Board. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 53: 1013-1026, 2018; DOI: 10.3892/ijo.2018.4467].
22 citations
TL;DR: It is suggested that curcumin may be a suitable natural product which may be used to overcome chemoresistance by inhibiting the CAF-induced activation of the JAK/STAT3 signaling pathway in GC.
Abstract: The present study aimed to investigate whether the Janus-activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is a critical mechanism underlying the cancer-associated fibroblast (CAF)-induced chemoresistance of gastric cancer (GC). In addition, the present study tried to suggest a natural product to compromise the effects of CAF on the chemoresistance of GC. The results of cell proliferation assay revealed that the conditioned medium (CM) collected from CAFs further increased resistance to 5-fluorouracil (5-FU) in GC cell lines. Secretome analysis revealed that the levels of several secreted proteins, including C-C motif chemokine ligand 2, C-X-C motif chemokine ligand 1, interleukin (IL)-6 and IL-8, were increased in the CM from CAFs co-cultured with cancer cells compared to CM from cancer cells. Western blot analysis revealed that CAFs activated the JAK/STAT3 signaling pathway in cancer cells. The experimental models revealed that curcumin abrogated the CAF-mediated activation of the JAK/STAT3 signaling pathway in GC cells. In vivo data revealed the synergistic effects of curcumin with 5-FU treatment in xenograft GC tumors. These data strongly suggest that the suppression of the JAK/STAT3 signaling pathway counteracts the CAF-induced chemoresistance of GC cells. It is suggested that curcumin may be a suitable natural product which may be used to overcome chemoresistance by inhibiting the CAF-induced activation of the JAK/STAT3 signaling pathway in GC.
16 citations
TL;DR: The present study aimed to provide an update of the current knowledge on the frequency of BRCA1/2 mutations and cancer susceptibility, focusing on the diagnostic potential of the most recent methods, such as ddPCR.
Abstract: Breast and ovarian cancer represent two of the most common tumor types in females worldwide. Over the years, several non-modifiable and modifiable risk factors have been associated with the onset and progression of these tumors, including age, reproductive factors, ethnicity, socioeconomic status and lifestyle factors, as well as family history and genetic factors. Of note, BRCA1 and BRCA2 are two tumor suppressor genes with a key role in DNA repair processes, whose mutations may induce genomic instability and increase the risk of cancer development. Specifically, females with a family history of breast or ovarian cancer harboring BRCA1/2 germline mutations have a 60-70% increased risk of developing breast cancer and a 15-40% increased risk for ovarian cancer. Different databases have collected the most frequent germline mutations affecting BRCA1/2. Through the analysis of such databases, it is possible to identify frequent hotspot mutations that may be analyzed with next-generation sequencing (NGS) and novel innovative strategies. In this context, NGS remains the gold standard method for the assessment of BRCA1/2 mutations, while novel techniques, including droplet digital PCR (ddPCR), may improve the sensitivity to identify such mutations in the hereditary forms of breast and ovarian cancer. On these bases, the present study aimed to provide an update of the current knowledge on the frequency of BRCA1/2 mutations and cancer susceptibility, focusing on the diagnostic potential of the most recent methods, such as ddPCR.
13 citations
TL;DR: The ability of macrophage to remodel the TME through interactions with other cells and corresponding changes in their number, activity, and phenotype during conventional therapies, as well as the association between these changes and drug resistance, make tumor-associated macrophages a new target for antitumor therapies.
Abstract: The number and phenotype of macrophages are closely related to tumor growth and prognosis. Macrophages are recruited to (and polarized at) the tumor site thereby promoting tumor growth, stimulating tumor angiogenesis, facilitating tumor cell migration, and creating a favorable environment for subsequent colonization by (and survival of) tumor cells. These phenomena contribute to the formation of an immunosuppressive tumor microenvironment (TME) and therefore speed up tumor cell proliferation and metastasis and reduce the efficacy of antitumor factors and therapies. The ability of macrophages to remodel the TME through interactions with other cells and corresponding changes in their number, activity, and phenotype during conventional therapies, as well as the association between these changes and drug resistance, make tumor-associated macrophages a new target for antitumor therapies. In this review, advantages and limitations of the existing antitumor strategies targeting macrophages in Traditional Chinese and Western medicine were analyzed, starting with the effect of macrophages on tumors and their interactions with other cells and then the role of macrophages in conventional treatments was explored. Possible directions of future developments in this field from an all-around multitarget standpoint were also examined.
12 citations
TL;DR: Understanding the 'Reverse Warburg effect' of CAFs and its related mechanisms will help to understand the association between the microenvironment, the matrix, and cancer cells, and may lead to new treatment strategies and targets.
Abstract: Metabolic reprogramming is one of the main characteristics of malignant tumors. The metabolic reprogramming of tumors is not only related to the characteristics of cancer cells, but also closely related to the tumor microenvironment (TME). 'Aerobic glycolysis' is considered to be the classic metabolic mode of tumor cells. However, recent experiments have shown that the TME plays a key role in carcinogenesis and epithelial‑mesenchymal transition. Cancer‑associated fibroblasts (CAFs) dominate in the microenvironment and affect the homeostasis of the TME. The interaction between cancer cells and the surrounding CAFs markedly affects the growth, metabolism, metastasis, and progression of cancer. Based on this, a 'dual‑chamber' model, also known as the 'Reverse Warburg effect', is proposed. Specifically, cancer cells secrete hydrogen peroxide into the TME to induce oxidative stress in neighboring stromal cells. CAFs undergo aerobic glycolysis and produce high levels of energy‑rich 'fuels' (such as pyruvate, ketone bodies, fatty acids, and lactic acid). In turn, these energy‑rich 'fuels' then 'feed' cancer cells. The mitochondrial oxidative phosphorylation system produces a large quantity of ATP, such that tumor cells have a higher proliferation ability. The proposed 'Reverse Warburg effect' redefines the tumor cell microenvironment and tumor metabolic reprogramming. Therefore, understanding the 'Reverse Warburg effect' of CAFs and its related mechanisms will help us to understand the association between the microenvironment, the matrix, and cancer cells, and may lead to new treatment strategies and targets.
12 citations
TL;DR: Results indicated that WBSCR22 played an important role in PC development and that the WBS CR22/ISG15 axis may provide a novel therapeutic strategy for PC treatment, and the oncogenic role of ISG15 was further confirmed in PC.
Abstract: Pancreatic cancer (PC) is one of the most aggressive and devastating types of cancer owing to its poor prognosis and deadly characteristics. It is well established that aberrations in the expression of key regulatory genes, namely tumor suppressors and oncogenes, predispose patients to progression and metastasis of PC. Upregulation of Williams-Beuren syndrome chromosomal region 22 (WBSCR22) expression, a ribosomal biogenesis factor, has been reported in multiple types of human cancer. However, the role of WBSCR22 and its underlying mechanism in PC have not been well investigated. In the present study, the tumor suppressive role of WBSCR22 was reported in PC for the first time; the results indicated that WBSCR22 overexpression (OE) significantly suppressed cellular proliferation, migration, invasion and tumorigenesis in vivo and in vitro. RNA-sequencing analysis revealed that WBSCR22 negatively regulated the transcription of interferon-stimulated gene 15 (ISG15) downstream, which is a ubiquitin-like modifier protein involved in metabolic and proteasome degradation pathways, while the antitumor function of WBSCR22-OE could be rescued by ISG15 OE. In addition, the oncogenic role of ISG15 was further confirmed in PC; its upregulation promoted the proliferation, migration, invasion and tumorigenesis of PC. Furthermore, WBSCR22 and its cofactor tRNA methyltransferase activator subunit 11-2 (TRMT112) functioned synergistically in PC, and concurrent ectopic OE of WBSCR22 and TRMT112 further promoted the tumor suppressive potential of WBSCR22 in PC. Collectively, the findings indicated that WBSCR22 played an important role in PC development and that the WBSCR22/ISG15 axis may provide a novel therapeutic strategy for PC treatment.
12 citations
TL;DR: There is an unmet requirement for further study into the processes of glioblastoma pathogenesis and the discovery of novel therapeutic targets in novel signaling pathways implicated in the evolution of glooblastomas.
Abstract: Glioblastoma multiforme (GBM) is the most aggressive type of primary brain tumor and is associated with a poor clinical prognosis. Despite the progress in the understanding of the molecular and genetic changes that promote tumorigenesis, effective treatment options are limited. The present review intended to identify and summarize major signaling pathways and genetic abnormalities involved in the pathogenesis of GBM, as well as therapies that target these pathways. Glioblastoma remains a difficult to treat tumor; however, in the last two decades, significant improvements in the understanding of GBM biology have enabled advances in available therapeutics. Significant genomic events and signaling pathway disruptions (NF-κB, Wnt, PI3K/AKT/mTOR) involved in the formation of GBM were discussed. Current therapeutic options may only marginally prolong survival and the current standard of therapy cures only a small fraction of patients. As a result, there is an unmet requirement for further study into the processes of glioblastoma pathogenesis and the discovery of novel therapeutic targets in novel signaling pathways implicated in the evolution of glioblastoma.
12 citations
TL;DR: In this paper , EGCG treatment of CAFs suppressed their tumor-promoting capabilities by inhibiting their glycolytic activity, indicating that lactate fulfills an important role in metabolic coupling that occurs between CAFs and cancer cells.
Abstract: In recent times, researchers working on tumor metabolism have paid increasing attention to the tumor microenvironment. Emerging evidence has confirmed that epigenetic modifications of cancer-associated fibroblasts (CAFs) alters the characteristics of glucose metabolism to achieve a symbiotic relationship with the cancer cells. Epigallocatechin-3-gallate (EGCG) exerts anti-tumor effects via a variety of mechanisms, although the underlying mechanism that accounts for the effects of EGCG on glucose metabolic alterations of CAFs have yet to be elucidated. In the present study, through co-culture with colorectal cancer (CRC) cells, human intestinal fibroblasts were transformed into CAFs, and exhibited enhanced aerobic glycolysis. Induced CAFs were able to enhance the proliferation, migration and invasion of CRC cells in vitro. EGCG treatment led to direct inhibition of the proliferation and migration of CRC cells; furthermore, EGCG treatment of CAFs suppressed their tumor-promoting capabilities by inhibiting their glycolytic activity. Blocking the lactic acid efflux of CAFs with a monocarboxylate transporter 4 (MCT4) inhibitor or through silencing MCT4 could also suppress their tumor-promoting capabilities, indicating that lactate fulfills an important role in the metabolic coupling that occurs between CAFs and cancer cells. Taken together, the results of the present study showed that EGCG targeting of the metabolism of tumor stromal cells provided a safe and effective strategy of anti-cancer therapy.
11 citations
TL;DR: The present review examines the recent studies that demonstrate the biological role of epigenetics, in particular, DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling in tumor progression and metastasis by regulating EMT status, and provides an overview of the current state of knowledge.
Abstract: Epigenetics is the study of heritable molecular determinants that are independent of phenotypic features. The epigenetic features include DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling. In multicellular organisms, the epigenetic state of a cell is critical in determining its differentiation status and its ability to perform its proper function. These processes are now well recognized as being a substantial factor in tumor progression and metastasis. The process through which epithelial cells acquire mesenchymal features is known as epithelial-mesenchymal transition (EMT). EMT is associated with tumorigenesis, invasion, metastasis, and resistance to therapy in cancer. In the present review, we examine the recent studies that demonstrate the biological role of epigenetics, in particular, DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling in tumor progression and metastasis by regulating EMT status, and we provide an overview of the current state of knowledge regarding the epigenetics involvement in tumor progression and metastasis. Because epigenetic changes can be reversed, learning more about their biological roles in EMT will not only help us better understand how cancer progresses and spreads, but it will also help us identify new ways to diagnose and treat human malignancy which is currently lacking in the clinical setting.
10 citations
TL;DR: The metabolic signatures observed in PC, a disease with a multifaceted and often transient metabolic landscape, are discussed, providing examples of how they could present novel targets for therapeutic interventions and elaborating on how interactions between the various cell types affect their metabolism.
Abstract: Pancreatic cancer (PC) has one of the highest fatality rates and the currently available therapeutic options are not sufficient to improve its overall poor prognosis. In addition to insufficient effectiveness of anticancer treatments, the lack of clear early symptoms and early metastatic spread maintain the PC survival rates at a low level. Metabolic reprogramming is among the hallmarks of cancer and could be exploited for the diagnosis and treatment of PC. PC is characterized by its heterogeneity and, apart from molecular subtypes, the identification of metabolic subtypes in PC could aid in the development of more individualized therapeutic approaches and may lead to improved clinical outcomes. In addition to the deregulated utilization of glucose in aerobic glycolysis, PC cells can use a wide range of substrates, including branched-chain amino acids, glutamine and lipids to fulfil their energy requirements, as well as biosynthetic needs. The tumor microenvironment in PC supports tumor growth, metastatic spread, treatment resistance and the suppression of the host immune response. Moreover, reciprocal interactions between cancer and stromal cells enhance their metabolic reprogramming. PC stem cells (PCSCs) with an increased resistance and distinct metabolic properties are associated with disease relapses and cancer spread, and represent another significant candidate for therapeutic targeting. The present review discusses the metabolic signatures observed in PC, a disease with a multifaceted and often transient metabolic landscape. In addition, the metabolic pathways utilized by PC cells, as well as stromal cells are discussed, providing examples of how they could present novel targets for therapeutic interventions and elaborating on how interactions between the various cell types affect their metabolism. Furthermore, the importance of PCSCs is discussed, focusing specifically on their metabolic adaptations.
TL;DR: The enrichment analysis revealed that ADAM12 is involved in multiple vital biological functions and pathways, such as 'macrophage activation', 'extracellular matrix binding' and 'ECM-receptor interaction', and highlighted the potential of ADAM 12 to be used as a therapeutic target for GC.
Abstract: A disintegrin and metalloprotease 12 (ADAM12), an essential transmembrane protein with metalloprotease, cell binding and intracellular signal-regulating capabilities, has been reported to play a crucial role in various types of cancers. However, the biological function of ADAM12 in gastric cancer (GC) remains unclear. Bioinformatic and experimental analyses were used to determine the expression level and prognostic value of ADAM12 in GC. The level of DNA methylation and the competing endogenous RNA (ceRNA) network was identified using MethSurv, Starbase3.0, miRNet2.0 and experimental analyses. Then, the co-expression profiles of ADAM12 were determined and subjected to enrichment analysis using the LinkedOmics database. The protein-protein interaction network and the docking model of ADAM12 were constructed using the GeneMANIA, STRING, and HDOCK webservers. The role of ADAM12 in tumor metastasis and immune infiltration was investigated using in vitro assays and TIMER database exploration. It was found that ADAM12 was overexpressed and was correlated with a poor prognosis of GC patients. In addition, the aberrant DNA methylation status and ceRNA regulation may contribute to the upregulation of ADAM12 in GC. Moreover, the enrichment analysis revealed that ADAM12 is involved in multiple vital biological functions and pathways, such as 'macrophage activation', 'extracellular matrix binding' and 'ECM-receptor interaction'. Subsequently, the protein-protein interaction network and molecular docking model demonstrated that follistatin like 3 (FSTL3) is a potential binding partner of ADAM12. Finally, it was demonstrated that ADAM12 promotes tumor metastasis, immune infiltration and M2 macrophage polarization in GC. In summary, these results highlight the potential of ADAM12 to be used as a therapeutic target for GC.
TL;DR: Insight is provided into stem cell-free molecular-targeted therapy based on bio-carrier NSC-EXOs and provides a potential strategy for the treatment of glioma.
Abstract: Currently, exosomes (EXOs) are being explored as novel drug delivery carriers with greater advantages, including crossing the blood-brain-barrier and loading drugs. The present study utilized EXOs derived from neural stem cells (NSCs) for the delivery of molecular drugs to treat gliomas. miR-124-3p was selected according to previous studies by the authors, and the effects of the delivery of miR-124-3p to glioma cells by NSC-EXOs in vitro and in vivo were evaluated. It was found that NSC-EXOs successfully delivered miR-124-3p into glioma cells, and NSC-EXOs loaded with miR-124-3p significantly inhibited glioma cell proliferation, invasion and migration. Furthermore, the delivery of miR-124-3p by NSC-EXOs suppressed flotillin 2 (FLOT2) expression by specifically binding to the 3' untranslated region of the FLOT2 gene in gliomas; subsequently, AKT1 was found to be associated with the EXO-miR-124-3p/FLOT2 pathway. Moreover, the therapeutic effects of the delivery of miR-124-3p by NSC-EXOs were confirmed in a mouse tumor xenograft model of glioma. Thus, bio-carrier NSC-EXOs loaded with miR-124-3p suppressed glioma growth via the EXO-miR-124-3p/FLOT2/AKT1 pathway. On the whole, the present study provides insight into stem cell-free molecular-targeted therapy based on bio-carrier NSC-EXOs and provides a potential strategy for the treatment of glioma.
TL;DR: In this paper , the expression and effect of miR-1291 in colorectal cancer (CRC) cells was investigated, and it was found that miR1291 significantly suppressed the proliferation, invasion, cell mobility and colony formation of CRC cells.
Abstract: miR-1291 exerts an anti-tumor effect in a subset of human carcinomas, including pancreatic cancer. However, its role in colorectal cancer (CRC) is largely unknown. In the present study, the expression and effect of miR-1291 in CRC cells was investigated. It was identified that miR-1291 significantly suppressed the proliferation, invasion, cell mobility and colony formation of CRC cells. Additionally, miR-1291 induced cell apoptosis. A luciferase reporter assay revealed that miR-1291 directly bound the 3′-untranslated region sequence of doublecortin-like kinase 1 (DCLK1). miR-1291 also suppressed DCLK1 mRNA and protein expression in HCT116 cells that expressed DCLK1. Furthermore, miR-1291 suppressed cancer stem cell markers BMI1 and CD133, and inhibited sphere formation. The inhibitory effects on sphere formation, invasion and mobility in HCT116 cells were also explored and verified using DCLK1 siRNAs. Furthermore, miR-1291 induced CDK inhibitors p21WAF1/CIP1 and p27KIP1 in three CRC cell lines, and the overexpression of DCLK1 in HCT116 cells led to a decrease of p21WAF1/CIP1 and p27KIP1. Intravenous administration of miR-1291 loaded on the super carbonate apatite delivery system significantly inhibited tumor growth in the DLD-1 xenograft mouse model. Additionally, the resultant tumors exhibited significant upregulation of the p21WAF1/CIP1 and p27KIP1 protein with treatment of miR-1291. Taken together, the results indicated that miR-1291 served an anti-tumor effect by modulating multiple functions, including cancer stemness and cell cycle regulation. The current data suggested that miR-1291 may be a promising nucleic acid medicine against CRC.
TL;DR: This combined organoid‑PDX approach is expected to be able to provide the drug sensitivity testing approach for individualization of prostate cancer therapy in the near future.
Abstract: Prostate cancer mortality is ranked second among all cancer mortalities in men worldwide. There is a great need for a method of efficient drug screening for precision therapy, especially for patients with existing drug‑resistant prostate cancer. Based on the concept of bacterial cell culture and drug sensitivity testing, the traditional approach of cancer drug screening is inadequate. The current and more innovative use of cancer cell culture and in vivo tumor models in drug screening for potential individualization of anti‑cancer therapy is reviewed and discussed in the present review. An ideal screening model would have the ability to identify drug activity for the targeted cells resembling what would have occurred in the in vivo environment. Based on this principle, three available cell culture/tumor screening models for prostate cancer are reviewed and considered. The culture conditions, advantages and disadvantages for each model together with ideas to best utilize these models are discussed. The first screening model uses conditional reprogramed cells derived from patient cancer cells. Although these cells are convenient to grow and use, they are likely to have different markers and characteristics from original tumor cells and thus not likely to be informative. The second model employs patient derived xenograft (PDX) which resembles an in vivo approach, but its main disadvantages are that it cannot be easily genetically modified and it is not suitable for high‑throughput drug screening. Finally, high‑throughput screening is more feasible with tumor organoids grown from patient cancer cells. The last system still needs a large number of tumor cells. It lacks in situ blood vessels, immune cells and the extracellular matrix. Based on these current models, future establishment of an organoid data bank would allow the selection of a specific organoid resembling that of an individual's prostate cancer and used for screening of suitable anticancer drugs. This can be further confirmed using the PDX model. Thus, this combined organoid‑PDX approach is expected to be able to provide the drug sensitivity testing approach for individualization of prostate cancer therapy in the near future.
TL;DR: It is determined that circ-LRP6 knockdown inhibited the proliferation, migration and invasion of OS cells by regulating the miR-141-3p/HDAC4/HMGB1 axis.
Abstract: Circular RNA-lipoprotein receptor 6 (circ-LRP6) serves a role in promoting the tumorigenesis of retinoblastoma, esophageal squamous cell cancer and oral squamous cell carcinoma; however, whether circ-LRP6 demonstrates the same effect in osteosarcoma (OS) is yet to be fully elucidated. The present study aimed to analyze the expression, role and potential molecular mechanism of circ-LRP6 in OS. The expression levels of circ-LRP6, microRNA (miR)-141-3p, histone deacetylase 4 (HDAC4) and high mobility group protein 1 (HMGB1) were evaluated by reverse transcription- quantitative PCR in OS tissues and cell lines. Cell Counting Kit-8, Transwell and Matrigel assays were conducted to evaluate cell proliferation, migration and invasion, respectively. Western blotting was also performed to determine HDAC4 and HMGB1 protein expression levels. Bioinformatics and dual-luciferase reporter assays were used to predict and analyze the interactions between circ-LRP6 and miR-141-3p, miR-141-3p and HDAC4, as well as between miR-141-3p and HMGB1. Additionally, RNA immunoprecipitation was performed to verify the association between circ-LRP6 and miR-141-3p. The results confirmed that circ-LRP6 was highly expressed in OS tissues and cell lines. In addition, circ-LRP6 negatively regulated the expression of miR-141-3p and, in turn, miR-141-3p negatively regulated HDAC4 and HMGB1 expression. Functional assays revealed that circ-LRP6 knockdown inhibited the proliferation, migration and invasion of OS cells, whereas the inhibition of miR-141-3p or the overexpression of either HDAC4 or HMGB1 partly reversed the inhibitory effect of circ-LRP6 knockdown. In summary, the present study determined that circ-LRP6 knockdown inhibited the proliferation, migration and invasion of OS cells by regulating the miR-141-3p/HDAC4/HMGB1 axis.
TL;DR:
Abstract: As the most common primary tumour of the central nervous system, gliomas have a high recurrence rate after surgical resection and are resistant to chemotherapy, particularly high-grade gliomas dominated by glioblastoma multiforme (GBM). The prognosis of GBM remains poor despite improvements in treatment modalities, posing a serious threat to human health. At present, although drugs such as temozolomide, cisplatin and bevacizumab, are effective in improving the overall survival of patients with GBM, most patients eventually develop drug resistance, leading to poor clinical prognosis. The development of multidrug resistance has therefore become a major obstacle to improving the effectiveness of chemotherapy for GBM. The ability to fully understand the underlying mechanisms of chemotherapy resistance and to develop novel therapeutic targets to overcome resistance is critical to improving the prognosis of patients with GBM. Of note, growing evidence indicates that a large number of abnormally expressed noncoding RNAs (ncRNAs) have a central role in glioma chemoresistance and may target various mechanisms to modulate chemosensitivity. In the present review, the roles and molecular mechanisms of ncRNAs in glioma drug resistance were systematically summarized, the potential of ncRNAs as drug resistance markers and novel therapeutic targets of glioma were discussed and prospects for glioma treatment were outlined. ncRNAs are a research direction for tumor drug resistance mechanisms and targeted therapies, which not only provides novel perspectives for reversing glioma drug resistance but may also promote the development of precision medicine for clinical diagnosis and treatment.
TL;DR: This study demonstrated that birinapant and carboplatin combination could target a subset of platinum-resistant ovarian cancers and also highlights the potential of the 3D organoid bioassay as a preclinical tool to assess the response to chemotherapy or targeted therapies in ovarian cancer.
Abstract: Patients diagnosed with epithelial ovarian cancers (EOCs) often suffer from disease relapse associated with the emergence of resistance to standard platinum-based chemotherapy. Treatment of patients with chemo-resistant disease remains a clinical challenge. One mechanism of chemoresistance includes overexpression of pro-survival proteins called inhibitors of apoptosis (IAP) which enable cancer cells to evade apoptosis. Due to their anti-apoptotic activity, association with poor prognosis, and correlation with therapy resistance in multiple malignancies, IAP proteins have become an attractive target for development of anticancer therapeutics. Second mitochondrial activator of caspase (SMAC) mimetics are the most widely used IAP antagonists currently being tested in clinical trials as a monotherapy and in combination with different chemotherapeutic drugs to target different types of cancer. In the present study, the antitumor efficacy of combination therapy with birinapant, a bivalent SMAC mimetic compound, and carboplatin to target platinum-resistant EOC cells was investigated. A 3D organoid bioassay was utilized to test the efficacy of the combination therapy in a panel of 7 EOC cell lines and 10 platinum-resistant primary patient tumor samples. Findings from the in vitro studies demonstrated that the birinapant and carboplatin combination was effective in targeting a subset of ovarian cancer cell lines and platinum-resistant primary patient tumor samples. This combination therapy was also effective in vitro and in vivo in targeting a platinum-resistant patient-derived xenograft (PDX) model established from one of the patient tumors tested. Overall, our study demonstrated that birinapant and carboplatin combination could target a subset of platinum-resistant ovarian cancers and also highlights the potential of the 3D organoid bioassay as a preclinical tool to assess the response to chemotherapy or targeted therapies in ovarian cancer.
TL;DR:
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly infectious and pathogenic. Among patients with severe SARS-CoV-2-caused by corona virus disease 2019 (COVID-19), those complicated with malignant tumor are vulnerable to COVID-19 due to compromised immune function caused by tumor depletion, malnutrition and anti-tumor treatment. Cancer is closely related to the risk of severe illness and mortality in patients with COVID-19. SARS-CoV-2 could promote tumor progression and stimulate metabolism switching in tumor cells to initiate tumor metabolic modes with higher productivity efficiency, such as glycolysis, for facilitating the massive replication of SARS-CoV-2. However, it has been shown that infection with SARS-CoV-2 leads to a delay in tumor progression of patients with natural killer cell (NK cell) lymphoma and Hodgkin's lymphoma, while SARS-CoV-2 elicited anti-tumor immune response may exert a potential oncolytic role in lymphoma patients. The present review briefly summarized potential carcinogenicity and oncolytic characteristics of SARS-CoV-2 as well as strategies to protect patients with cancer during the COVID-19 pandemic.
TL;DR: Understanding the roles and mechanisms of exosomes in HCC progression and radiation response during HCC therapy may increase knowledge concerning the roles of exOSomes in radioresistance, and may lead to novel approaches for HCC prognosis and treatment.
Abstract: The incidence rates of hepatocellular carcinoma (HCC) worldwide are increasing, and the role of radiotherapy is currently under discussion. Radioresistance is one of the most important challenges in the therapy of HCC compared with other local advanced, recurrent and metastatic cancers. The mechanisms of radioresistance are complex and remain to be fully understood; however, extracellular vesicles have been investigated in recent studies. Exosomes, which are 40- to 150-nm extracellular vesicles released by cancer cells, contain multiple pathogenic components, including proteins, nucleic acids and lipids, and play critical functions in cancer progression. Emerging data indicate a diagnosis potential for exosomes in HCC, since radiation-derived exosomes promote radioresistance. Radiation-based therapy alters the contents and components of exosomes, suggesting that exosomes and their components may serve as prognostic and predictive biomarkers to monitor radiation response. Therefore, understanding the roles and mechanisms of exosomes in HCC progression and radiation response during HCC therapy may increase our knowledge concerning the roles of exosomes in radioresistance, and may lead to novel approaches for HCC prognosis and treatment. The current review summarizes recent studies on exosome involvement in HCC and the molecular changes in exosome components during HCC progression. It also discusses the functions of exosomes in HCC therapy, and highlights the importance of exosomes in HCC progression and resistance for the development of novel therapies.
TL;DR: Recent updates on the functional role of circRNAs in terms of the technological landscape, clinical opportunities (biomarkers and therapeutic targets), and challenges in cancer have been illustrated.
Abstract: Circular RNAs (circRNAs) are a novel class of endogenous non‑coding RNAs that have been recently regarded as functionally active. CircRNAs are remarkably stable and known to possess several biological functions such as microRNA sponging, regulating transcription and splicing and occasionally acting as polypeptide‑producing templates. CircRNAs show tissue‑specific expression and have been reported to be associated with the progression of several types of malignancies. Given the recent progress in genome sequencing and bioinformatics techniques, a rapid increment in the biological role of circRNAs has been observed. Concurrently, the patent search from different patent databases shows that the patent number of circRNA is increasing very quickly. These phenomena reveal a rapid development of the technological landscape. In the present review, the recent progress on circRNAs in various kinds of cancer has been investigated and their function as biomarkers or therapeutic targets and their technological landscape have been appreciated. A new insight into circRNAs structure and functional capabilities in cancer has been reviewed. Continually increasing knowledge on their critical role during cancer progression is projecting them as biomarkers or therapeutic targets for various kinds of cancer. Thus, recent updates on the functional role of circRNAs in terms of the technological landscape, clinical opportunities (biomarkers and therapeutic targets), and challenges in cancer have been illustrated.
TL;DR: New insights into the substrates for ubiquitination that are involved in the regulation of hypoxic environments, angiogenesis, chronic inflammation-mediated tumor formation, and the function of cancer-associated fibroblasts and infiltrating immune cells are summarized.
Abstract: The interaction between a tumor and the tumor microenvironment (TME) plays a key role in tumorigenesis and tumor progression. Ubiquitination, a crucial post-translational modification for regulating protein degradation and turnover, plays a role in regulating the crosstalk between a tumor and the TME. Thus, identifying the roles of ubiquitination in the process may assist researchers to investigate the mechanisms underlying tumorigenesis and tumor progression. In the present review article, new insights into the substrates for ubiquitination that are involved in the regulation of hypoxic environments, angiogenesis, chronic inflammation-mediated tumor formation, and the function of cancer-associated fibroblasts and infiltrating immune cells (tumor-associated macrophages, T-cells, myeloid-derived suppressor cells, dendritic cells, and natural killer cells) are summarized. In addition, the potential targets of the ubiquitination proteasome system within the TME for cancer therapy and their therapeutic effects are reviewed and discussed.
TL;DR: The intrinsic properties of low immunogenicity and high stability render s EVs ideal vehicles for targeted drug delivery in the treatment of HCC and the potential and prospective diagnostic and therapeutic applications of sEVs in HCC are discussed.
Abstract: Hepatocellular carcinoma (HCC) is the most common malignancy of hepatocytes accounting for 75-85% of primary hepatic carcinoma cases. Small extracellular vesicles (sEVs), previously known as exosomes with a diameter of 30-200 nm, can transport a variety of biological molecules between cells, and have been proposed to function in physiological and pathological processes. Recent studies have indicated that the cargos of sEVs are implicated in intercellular crosstalk among HCC cells, paratumor cells and the tumor microenvironment. sEV-encapsulated substances (including DNA, RNA, proteins and lipids) regulate signal transduction pathways in recipient cells and contribute to cancer initiation and progression in HCC. In addition, the differential expression of sEV cargos between patients facilitates the potential utility of sEVs in the diagnosis and prognosis of patients with HCC. Furthermore, the intrinsic properties of low immunogenicity and high stability render sEVs ideal vehicles for targeted drug delivery in the treatment of HCC. The present review article summarizes the carcinogenic and anti-neoplastic capacities of sEVs and discusses the potential and prospective diagnostic and therapeutic applications of sEVs in HCC.
TL;DR: The results of the present study suggest that miR-382 may alter the metabolic status of macrophages by targeting PGC-1α, thereby decreasing the proportion of TAMs with the M2 phenotype, and inhibiting the progression and metastasis of breast cancer.
Abstract: Macrophages are principal immune cells with a high plasticity in the human body that can differentiate under different conditions in the tumor microenvironment to adopt two polarized phenotypes with opposite functions. Therefore, converting macrophages from the immunosuppressive phenotype (M2) to the inflammatory phenotype (M1) is considered a promising therapeutic strategy for cancer. However, the molecular mechanisms underlying this conversion process have not yet been completely elucidated. In recent years, microRNAs (miRNAs or miRs) have been shown to play key roles in regulating macrophage polarization through their ability to modulate gene expression. In the present study, it was found that miR-382 expression was significantly downregulated in tumor-associated macrophages (TAMs) and M2-polarized macrophages in breast cancer. In vitro, macrophage polarization toward the M2 phenotype and M2-type cytokine release were inhibited by transfection with miR-382-overexpressing lentivirus. Similarly, the overexpression of miR-382 inhibited the ability of TAMs to promote the malignant behaviors of breast cancer cells. In addition, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) was identified as the downstream target of miR-382 and it was found that PGC-1α affected macrophage polarization by altering the metabolic status. The ectopic expression of PGC-1α restored the phenotype and cytokine secretion of miR-382-overexpressing macrophages. Furthermore, PGC-1α expression reversed the miR-382-induced changes in the metabolic state of TAMs and the effects of TAMs on breast cancer cells. Of note, the in vivo growth and metastasis of 4T1 cells were inhibited by miR-382-overexpressing TAMs. Taken together, the results of the present study suggest that miR-382 may alter the metabolic status of macrophages by targeting PGC-1α, thereby decreasing the proportion of TAMs with the M2 phenotype, and inhibiting the progression and metastasis of breast cancer.
TL;DR: In this article , the typical immune-related adverse events (irAEs) reported in recent years and the management strategies adopted are highlighted, to serve as a reference in assessing the clinical response to these adverse reactions.
Abstract: In 2020, there were an estimated 19.3 million new cancer cases and close to 10 million cancer deaths worldwide. Cancer remains one of the leading causes of death. In recent years, with the continuous improvement of our understanding of tumor immunotherapy, immunotherapeutics, such as immune checkpoint inhibitors, have gradually become a hot spot for tumor treatment. Amongst these, programmed cell death protein 1/programmed cell death protein ligand 1 (PD‑1/PD‑L1) related inhibitors, such as nivolumab and pembrolizumab, atezolizumab, avelumab and durvalumab have been shown to exhibit a high level of efficacy in several types of tumors. It has been confirmed that these inhibitors play an important role in the anti‑tumor process, significantly improving the survival rate of patients and delaying the progress of the underlying cancer. However, its method of therapeutic interference and potential for damaging the immune system has caused concern regarding its suitability. As these adverse effects are caused by an immune response to endogenous tissues, they are designated as immune‑related adverse events (irAEs). In this review, the typical irAEs reported in recent years and the management strategies adopted are highlighted, to serve as a reference in assessing the clinical response to these adverse reactions.
TL;DR: Classical and CYP11A1-derived vitamin D3-derivatives exhibited anticancer-activities on skin cancer cell lines and inhibited GLI1 and β-catenin signaling in a manner that was dependent on the position of hydroxyl groups.
Abstract: Hydroxyderivatives of vitamin D3, including classical 1,25(OH)2D3 and novel CYP11A1-derived hydroxyderivatives, exert their biological activity by acting as agonists on the vitamin D receptor (VDR) and inverse agonists on retinoid-related orphan receptors (ROR)α and γ. The anti-cancer activities of CYP11A1-derived hydroxyderivatives were tested using cell biology, tumor biology and molecular biology methods in human A431 and SCC13 squamous (SCC)- and murine ASZ001 basal (BCC)-cell carcinomas, in comparison with classical 1,25(OH)2D3. Vitamin D3-hydroxyderivatives with or without a C1α(OH) inhibited cell proliferation in a dose-dependent manner. While all the compounds tested had similar effects on spheroid formation by A431 and SCC13 cells, those with a C1α(OH) group were more potent in inhibiting colony and spheroid formation in the BCC line. Potent anti-tumorigenic activity against the BCC line was exerted by 1,25(OH)2D3, 1,20(OH)2D3, 1,20,23(OH)3D3, 1,20,24(OH)3D3, 1,20,25(OH)3D3 and 1,20,26(OH)3D3, with smaller effects seen for 25(OH)D3, 20(OH)D3 and 20,23(OH)2D3. 1,25(OH)2D3, 1,20(OH)2D3 and 20(OH)D3 inhibited the expression of GLI1 and β-catenin in ASZ001 cells. In A431 cells, these compounds also decreased the expression of GLI1 and stimulated involucrin expression. VDR, RORγ, RORα and CYP27B1 were detected in A431, SCC13 and ASZ001 lines, however, with different expression patterns. Immunohistochemistry performed on human skin with SCC and BCC showed nuclear expression of all three of these receptors, as well as megalin (transmembrane receptor for vitamin D-binding protein), the level of which was dependent on the type of cancer and antigen tested in comparison with normal epidermis. Classical and CYP11A1-derived vitamin D3-derivatives exhibited anticancer-activities on skin cancer cell lines and inhibited GLI1 and β-catenin signaling in a manner that was dependent on the position of hydroxyl groups. The observed expression of VDR, RORγ, RORα and megalin in human SCC and BCC suggested that they might provide targets for endogenously produced or exogenously applied vitamin D hydroxyderivatives and provide excellent candidates for anti-cancer therapy.
TL;DR: Mechanistic analyses indicated that TRIM35 regulates the transition of tetramers and dimers of pyruvate kinase M2 (PKM2) through ubiquitination and thereby affects the Warburg effect.
Abstract: Breast cancer has become the leading cause of death in females. After comprehensive treatment, the lives of patients are still threatened by tumor metastasis and recurrence. Therefore, there is an urgent requirement to find an effective treatment target for breast cancer. Tripartite motif-containing 35 (TRIM35) is a ubiquitin ligase that has an important role in the recurrence and metastasis of malignant tumors. However, the role of TRIM35 in breast cancer has thus far remained elusive. The expression of TRIM35 was examined in a bioinformatics database and the effects of TRIM35 on the malignant biological behavior of breast cancer were analyzed by Cell Counting Kit-8, cell migration and invasion assays, flow cytometry and nude mouse xenograft experiments. It was determined that TRIM35 was downregulated in breast cancer tumor tissues and cell lines. Patients with low TRIM35 expression had shorter overall survival. Functional assays revealed that overexpression of TRIM35 inhibited the proliferation, migration and invasion, and promoted apoptosis of breast cancer cells. Furthermore, overexpression of TRIM35 was able to inhibit the Warburg effect in breast cancer cells. Mechanistic analyses indicated that TRIM35 regulates the transition of tetramers and dimers of pyruvate kinase M2 (PKM2) through ubiquitination and thereby affects the Warburg effect. In conclusion, the present results indicated that TRIM35 regulates the tetramer and dimer transition of PKM2 through ubiquitination and affects the malignant biological behavior of breast cancer by modulating the Warburg effect.
TL;DR: It is found that lower TMPRSS2 expression in tumor compared to adjacent non-tumor tissues is linked to a poor overall survival in patients with adenocarcinoma (ADC) and those who are current smokers.
Abstract: Transmembrane serine protease 2 (TMPRSS2) has been intensively investigated during the current Sars-CoV-2 pandemic as a virus activating protease. Furthermore, TMPRSS2 is an oncogenic gene associated with several cancer entities. Co-expression of TMPRSS2 and serpin family A member 1 (SERPINA1) (encoding alpha-1-antitrypsin; AAT) has been reported in the human lung. Recently, AAT was identified as a novel TMPRSS2 inhibitor. We previously reported that lower SERPINA1 expression in tumor tissues and higher levels of plasma AAT are associated with worse survival of patients with non-small cell lung cancer (NSCLC). In the present study, we sought to examine TMPRSS2 and SERPINA1/AAT expression in tumor and adjacent lung tissues from 347 NSCLC patients. Based on clinical data and gene expression analysis, we performed Cox regression for the survival analysis, and correlated TMPRSS2 and AAT protein levels in tissue samples by immunohistochemical and western blot analyses. We found that lower TMPRSS2 expression in tumor compared to adjacent non-tumor tissues is linked to a poor overall survival in patients with adenocarcinoma (ADC) and those who are current smokers. IHC staining of TMPRSS2 validated our findings in regard to overall survival while we did not observe a correlation with AAT staining. Based on western blot analyses, we found only a slight negative correlation between full-length TMPRSS2 and AAT in non-tumor tissues, which seems to be related to smoking status. Taken together, we demonstrated that TMPRSS2 is a prognostic factor in patients with lung ADC; however, a link between AAT and TMPRSS2 proteins warrants further investigation.
TL;DR: Light is shed on the differential pathways regulating carcinogenesis in ERα(+) and ERβ(−) breast cancer patients and could help identify therapeutic targets selectively effective in ER α(+) vs. ERα (−) patients.
Abstract: The oxidoreductase protein disulfide isomerase A1 (PDIA1) functions as a cofactor for many transcription factors including estrogen receptor α (ERα), nuclear factor (NF)-κB, nuclear factor erythroid 2-like 2 (NRF2) and regulates the protein stability of the tumor suppressor p53. Taking this into account we hypothesized that PDIA1, by differentially modulating the gene expression of a diverse subset of genes in the ERα-positive vs. the ERα-negative breast cancer cells, might modify dissimilar pathways in the two types of breast cancer. This hypothesis was investigated using RNA-seq data from PDIA1-silenced MCF-7 (ERα-positive) and MDA-MB-231 (ERα-negative) breast cancer cells treated with either interferon γ (IFN-γ) or etoposide (ETO), and the obtained data were further analyzed using a variety of bioinformatic tools alongside clinical relevance assessment via Kaplan-Meier patient survival curves. The results highlighted the dual role of PDIA1 in suppressing carcinogenesis in the ERα(+) breast cancer patients by negatively regulating the response to reactive oxygen species (ROS) and promoting carcinogenesis by inducing cell cycle progression. In the ERα(−) breast cancer patients, PDIA1 prevented tumor development by modulating NF-κB and p53 activity and cell migration and induced breast cancer progression through control of cytokine signaling and the immune response. The findings reported in this study shed light on the differential pathways regulating carcinogenesis in ERα(+) and ERα(−) breast cancer patients and could help identify therapeutic targets selectively effective in ERα(+) vs. ERα(−) patients.
TL;DR: The findings of the present study indicate that ccRCC cells require CDCA5 for malignant progression, and thatCDCA5 inhibition may enhance the outcomes of patients with high-risk ccR CC.
Abstract: Cell division cycle-associated 5 (CDCA5) protein, which is involved in cohesion, contributes to cell cycle regulation and chromosome segregation by maintaining genomic stability. Accumulating evidence indicates that CDCA5 expression is upregulated in a number of types of cancer associated with a poor prognosis. However, the biological function of CDCA5 in clear cell renal cell carcinoma (ccRCC) remains largely unknown. In the present study, The Cancer Genome Atlas data mining revealed that CDCA5 was more highly expressed in ccRCC than in adjacent normal tissues. Importantly, such a high expression was associated with a higher risk of distant metastasis and poorer clinical outcomes. Moreover, the clinical and prognostic value of CDCA5 expression was further investigated using immunohistochemistry on tissue microarrays containing paired tumor tissues and adjacent normal tissues from 137 patients with ccRCC. Functional analyses revealed that CDCA5 knockdown significantly inhibited the proliferation and migration of ccRCC cells, and suppressed the growth of xenografts in nude mice. Mechanistically, CDCA5 knockdown induced severe DNA damage with the persistent accumulation of γ-H2A histone family member X foci, resulting in G2/M cell cycle arrest and finally, in chromosomal instability and apoptosis. CDCA5 knockdown significantly decreased the phosphorylation levels of Stat3 and NF-κB, suggesting that CDCA5 plays a role in regulating the inflammatory response. Collectively, the findings of the present study indicate that ccRCC cells require CDCA5 for malignant progression, and that CDCA5 inhibition may enhance the outcomes of patients with high-risk ccRCC.