Showing papers in "Cancer Biology & Therapy in 2021"
TL;DR: The immunotherapies recently approved by the FDA (ipilimumab, nivolumab and pembrolizumab) are compared with the long-approved immunotherapy, interleukin-2.
Abstract: Treatment of metastatic melanoma has changed dramatically in the past 5 years with the approval of six new agents (vemurafenib, dabrafenib, trametinib, ipilimumab, pembrolizumab, and nivolumab) by the US Food and Drug Administration (FDA). This review will compare the immunotherapies recently approved by the FDA (ipilimumab, nivolumab and pembrolizumab) with the long-approved immunotherapy, interleukin-2. Additional consideration will be given to the evolving landscape, including the opportunities for combination regimens. Immunotherapies have distinct mechanisms of action and unique response kinetics that differ from conventional cytotoxic and targeted therapies, and have a range of adverse events that can be safely managed by experienced health care providers. Data suggest immunotherapies can result in long-term survival in a proportion of patients. This dynamic and evolving field of immunotherapy for melanoma will continue to offer challenges in terms of optimal patient management for the fores...
27 citations
TL;DR: In this article, the detailed in vitro and in vivo anti-tumor effects of trametinib were investigated by using this model, and the data suggested a new strategy of tratinib-YAP inhibitor or tratenib-carboplatin combination as a promising treatment of bladder cancer.
Abstract: Bladder cancer (BC), a main neoplasm of urinary tract, is usually inoperable and unresponsive to chemotherapy. As a novel experimental model for muscle-invasive BC, we previously established a culture method of dog BC organoids. In the present study, the detailed in vitro and in vivo anti-tumor effects of trametinib were investigated by using this model. In each BC organoid strain, epidermal growth factor receptor (EGFR)/ERK signaling was upregulated compared with normal bladder cells. Trametinib even at a low concentration inhibited the cell viability of BC organoids and the activation of ERK through decreasing expression of c-Myc, ELK1, SIK1, and PLA2G4A. Trametinib arrested cell cycle of BC with few apoptosis. Dual treatment of BC organoids with trametinib and YAP inhibitor, verteporfin extremely inhibited the cell viability with apoptosis induction. Moreover, trametinib induced basal to luminal differentiation of BC organoids by upregulating luminal markers and downregulating basal ones. In vivo, trametinib decreased the tumor growth of BC organoids in mice and the xenograft-derived organoids from trametinib-administered mice showed enhanced sensitivity to carboplatin due to MSH2 upregulation. Our data suggested a new strategy of trametinib-YAP inhibitor or trametinib-carboplatin combination as a promising treatment of BC.
25 citations
TL;DR: In this article, the effects of DUXAP8 silencing on TNBC cell proliferation and apoptosis were identified using CCK-8 assay, EdU assay, flow cytometry analysis and TUNEL assay.
Abstract: Double homeobox A pseudogene 8 (DUXAP8) belongs to long non-coding RNAs (lncRNAs), which has been proven to promote the biological processes of multiple human cancers. Triple-negative breast cancer (TNBC) is the leading cause of cancer-related death in women worldwide. However, the specific role of lncRNA DUXAP8 and its underlying mechanism in TNBC remains to be unclear. We detected the expression of DUXAP8 in TNBC cells through qRT-PCR analysis. The effects of DUXAP8 silencing on TNBC cell proliferation and apoptosis were identified using CCK-8 assay, EdU assay, flow cytometry analysis and TUNEL assay. The downstream microRNA (miRNA) and messenger RNA (mRNA) of DUXAP8 were searched out through bioinformatics analysis and mechanism experiments. Rescue assays were conducted to verify the involvement of suppressor APC domain containing 2 (SAPCD2) in DUXAP8-mediated TNBC cell proliferation and apoptosis. DUXAP8 was highly expressed in TNBC cells compared to that in normal breast cells. Knockdown of DUXAP8 inhibited TNBC cell proliferation and accelerated cell apoptosis. DUXAP8 interacted with miR-29a-3p and thus enhanced the expression of SAPCD2. Moreover, YY1 transcription factor could bind to DUXAP8 promoter to activate the transcription of DUXAP8. YY1-induced transcriptional activation of DUXAP8 promotes TNBC cell growth through miR-29a-3p/SAPCD2 axis.
17 citations
TL;DR: Gold nanoparticles (AuNPs) have been shown to enhance cancer radiotherapy (RT) gain by localizing the absorption of radiation energy in the tumor while sparing surrounding normal tissue from radiat...
Abstract: Gold nanoparticles (AuNPs) have been shown to enhance cancer radiotherapy (RT) gain by localizing the absorption of radiation energy in the tumor while sparing surrounding normal tissue from radiat...
16 citations
TL;DR: This study found that HIF-1α, CXCL6, and CXCR2 expression levels were elevated in human brain microvascular endothelial cells (HBMECs) after IRI, whereas silent information regulator of transcription (Sirt) 3 expression level had reduced.
Abstract: Chemokine (C-X-C motif) ligand 6 (CXCL6), a member of the CXC chemokine family, reportedly mediates several processes such as inflammation, immunoreaction, cell growth, and metastasis through interaction with the chemokine receptors CXCR1 and CXCR2 in humans; further, CXCR1 and CXCR2 can promote repair and regeneration of organs or tissues after ischemia-reperfusion injury (IRI). In this study, we found that HIF-1α, CXCL6, and CXCR2 expression levels were elevated in human brain microvascular endothelial cells (HBMECs) after IRI, whereas silent information regulator of transcription (Sirt) 3 expression level had reduced. HIF-1α inhibition in an IRI model potently promoted HBMEC proliferation, accompanied by increased Sirt3 and decreased CXCL6/CXCR2 expression levels. CXCL6 knockdown in the IRI model significantly decreased HBMEC permeability and promoted HBMEC proliferation, concurrent with a decrease in apoptosis; it also increased Sirt3 expression levels and decreased CXCL6/CXCR2 protein and phosphorylated AKT (p-AKT) and class O of forkhead box (FOXO) 3a (p-FOXO3a) levels. In addition, CXCL6-induced HBMEC permeability and inhibition of HBMEC proliferation were counteracted by Sirt3 overexpression, and the AKT inhibitor LY294002 counteracted the effect of CXCL6 recombinant proteins on Sirt3, p-AKT, and p-FOXO3a expressions. These results suggest that CXCL6 and Sirt3 are downstream of HIF-1α and that CXCL6 regulatesHBMEC permeability, proliferation, and apoptosis after IRI by modulating Sirt3 expression via AKT/FOXO3a activation.
15 citations
TL;DR: Cancer stem cells (CSCs) represent a small subpopulation of cells found within tumors that exhibit properties of self-renewal, like normal stem cells.
Abstract: Cancer stem cells (CSCs) represent a small subpopulation of cells found within tumors that exhibit properties of self-renewal, like normal stem cells. CSCs have been defined as a crucial factor inv...
13 citations
TL;DR: Downregulation of HMGA2 inhibits the migration and invasion of TNBC and invivo tumor metastasis mediated through inhibition of EMT and Hippo-YAP pathway.
Abstract: Breast cancer is the most common cancer in women, and triple-negative breast cancer (TNBC) accounts for about 15–20% of all breast cancer. High mobility group AT-hook 2 (HMGA2) is overexpressed in ...
12 citations
TL;DR: In this article, NSUN6 methylates both large and small RNA in glioblastoma and controls response to temozolomide with or without influence of the MGMT promoter status.
Abstract: Nop2/Sun RNA methyltransferase (NSUN6) is an RNA 5-methyl cytosine (5mC) transferase with little information known of its function in cancer and response to cancer therapy. Here, we show that NSUN6 methylates both large and small RNA in glioblastoma and controls glioblastoma response to temozolomide with or without influence of the MGMT promoter status, with high NSUN6 expression conferring survival benefit to glioblastoma patients and in other cancers. Mechanistically, our results show that NSUN6 controls response to TMZ therapy via 5mC-mediated regulation of NELFB and RPS6BK2. Taken together, we present evidence that show that NSUN6-mediated 5mC deposition regulates transcriptional pause by accumulation of NELFB and the general transcription factor complexes (POLR2A, TBP, TFIIA, and TFIIE) on the preinitiation complex at the TATA binding site to control translation machinery in glioblastoma response to alkylating agents. Our findings open a new frontier into controlling of transcriptional regulation by RNA methyltransferase and 5mC.
12 citations
TL;DR: A bibliometric study is executed to identify the authors, journals, countries and institutions that contributed most to the top 100 lncRNAs list, characterize the key words and focus of top 100 most-cited papers, and detect the factors related to their successful citation.
Abstract: Up to 90% of the human genome is transcribed into Long-noncoding RNAs (lncRNAs) that longer than 200 nucleotides but do not code for proteins. LncRNAs play a vital role in a broad range of biological process, it's dysregulations and mutations are linked to the development and progression of various complex human diseases. Given the dramatic changes and growing scientific outputs in lncRNAs field, using a quantitative measurement to analyze and characterize the existing studies has become imperative.Bibliometric analysis is a widely used tool to assess the academic influence of a publication or a country in a specific field. However, a bibliometric analysis of the top 100 most-cited papers in lncRNAs area has not been conducted. Thus, we executed a bibliometric study to identify the authors, journals, countries and institutions that contributed most to the top 100 lncRNAs list, characterize the key words and focus of top 100 most-cited papers, and detect the factors related to their successful citation. This study provides a comprehensive list of the most influential papers on lncRNAs research and demonstrates the important advances in this field, which might be benefit to researchers in their paper publication and scientific cooperation.
11 citations
TL;DR: In this paper, the rationale and ongoing clinical trials of novel combination strategies involving chemotherapy, poly ADP ribose polymerase, programmed death 1 (PD-1)/PD-ligand 1 immune checkpoint and/or vascular endothelial growth factor receptor inhibitors are reviewed.
Abstract: Recently approved therapies have contributed to a significant progress in the management of ovarian cancer; yet, more options are needed to further improve outcomes in patients with advanced disease. Here we review the rationale and ongoing clinical trials of novel combination strategies involving chemotherapy, poly ADP ribose polymerase, programmed death 1 (PD-1)/PD-ligand 1 immune checkpoint and/or vascular endothelial growth factor receptor inhibitors. Further, we discuss novel agents aimed at targets associated with ovarian cancer growth or progression that are emerging as potential new treatment approaches. Among them, agents targeted to folate receptor α, tissue factor, and protein kinase-mediated pathways (WEE1 kinase, phosphatidylinositol-3 kinase α, cell cycle checkpoint kinase 1/2, ATR kinase) are currently in clinical development as mono- or combination therapies. If successful, findings from these extensive development efforts may further transform treatment of patients with advanced ovarian cancer.
10 citations
TL;DR: The nucleophosmin 1 (NPM1) protein is frequently overexpressed in various cancers compared to normal tissues and represents a potential biomarker for maliganancy as discussed by the authors.
Abstract: The nucleophosmin 1 (NPM1) protein is frequently overexpressed in various cancers compared to normal tissues and represents a potential biomarker for maliganancy. However, its role in colorectal ca...
TL;DR: In this article, specific biological functions and latent mechanism of FGD5 antisense RNA 1 (FGD5-AS1) were not yet clear in pancreatic cancer (PC) progression.
Abstract: In recent years, FGD5 antisense RNA 1 (FGD5-AS1) was confirmed to be the long non-coding RNAs (lncRNAs) that could accelerate the development of multiple cancers Nevertheless, specific biological functions and latent mechanism of FGD5-AS1 were not yet clear in pancreatic cancer (PC) This research was aimed to search the functions of FGD5-AS1 on the PC progression The expression of FGD5-AS1 in PC cells was tested by using RT-qPCR assay Colony formation assay, EdU assay, flow cytometry assay and transwell assay as well as western blot were adopted to test the cell abilities of proliferation, apoptosis and migration, separately Furthermore, RIP experiment and pull down assay were applied for validating the correlation FGD5-AS1, miR-520a-3p and KIAA1522 As a result, the abnormal high expression of FGD5-AS1 was observed in PC cells And cell proliferative and migratory abilities could be restrained via FGD5-AS1 depletion Moreover, FGD5-AS1 was proven to combine with miR-520a-3p directly It was also confirmed that KIAA1522 could be targeted by miR-520a-3p Rescue assay results indicated that overexpressed KIAA1522 could reverse the repressive function of silencing FGD5-AS1 on PC progression Taken together, FGD5-AS1 accelerated cell proliferation and migration via sponging miR-520a-3p and upregulating KIAA1522
TL;DR: In this article, the authors used sonoporation to enhance the efficacy of chemotherapy for pancreatreatic ductal adenocarcinoma (PDAC) in the modern world.
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the modern world, in part due to poor delivery of chemotherapeutics. Sonoporation can be used to enhance the efficacy of s...
TL;DR: Containing etoposide is beneficial in the initial treatment of LAHS, weather using the HLH directed or lymphoma directed strategy, and provides higher response rate, lower mortality rate and better survival, especially for EBV negative patients.
Abstract: Hemophagocytic lymphohistiocytosis (HLH) is a severe or even fatal inflammatory status caused by a hereditary or acquired immunoregulatory abnormality. Lymphoma-associated hemophagocytic lymphohistiocytosis (LAHS) is a kind of secondary HLH (sHLH). It suffers the worst outcome among sHLH. However, there is no standard treatment strategy. The argument mainly focuses on whether an HLH-directed or malignancy-directed approach should initially be adopted. Etoposide is one of the key drugs in HLH treatment and also shows activity in lymphomas. We sought to identify the importance of containing etoposide in the initial treatment of LAHS. 66 patients diagnosed with LAHS in our center during the three years were divided into two groups according to whether the initial treatment involved etoposide or lymphoma-directed chemotherapy without etoposide. The remission rate of the initial etoposide group (52 patients) is significantly better than that of the no initial etoposide group (14 patients) (73.1% vs. 42.9%, p = .033). The two-month survival rate (79.8% vs. 46.8%, p = .035) and overall survival (median survival time 25.8 w vs. 7.8 w, p = .048) of the initial etoposide contained group is significantly better. Multivariate cox analysis revealed that for patients without EBV infection (37 cases), initial treatment with etoposide could significantly improve prognosis (p = .010, Exp(B) = 0.183), but for patients with positive EBV, it shows a tendency. Containing etoposide is beneficial in the initial treatment of LAHS, whether in the HLH-directed or lymphoma-directed strategy. It provides higher response rate, lower mortality rate, and better survival, especially for EBV negative patients.
TL;DR: Four cases of refractory advanced intrahepatic or hilar cholangiocarcinoma were successfully controlled with anti-PD-1 antibody following or concurrent with SBRT and this combination may represent a breakthrough in the treatment of this fatal malignancy.
Abstract: Cholangiocarcinoma (CCA) represents a clinically challenging disease with a dismal prognosis. A therapeutic plateau has been reached with traditional treatments. However, with immunotherapy advances in cancer therapy, integration of stereotactic body radiotherapy (SBRT) with anti-PD-1 antibody shows a synergistic effect and high clinical efficacy in many cancer types. This combination may represent a breakthrough in the treatment of this fatal malignancy. Here, we report four cases of refractory advanced intrahepatic or hilar cholangiocarcinoma that were successfully controlled with anti-PD-1 antibody following or concurrent with SBRT. Furthermore, one case was initially unresectable; however, following this novel combined therapy, it became operable. We discuss the challenges of developing predictive biomarkers for anti-PD-1 antibody responsiveness. We also consider the regulatory effect of SBRT on the tumor microenvironment and the potential advantages of this therapy combination for treatment of intrahepatic or hilar cholangiocarcinoma. These are important considerations and provide direction for future clinical trial designs.
TL;DR: In this article, extracellular DNA or circulating cell-free DNA is considered to be a molecule with clinical applications (diagnosis, prognosis, monitoring of treatment responses, or patient follow-up).
Abstract: Nowadays, extracellular DNA or circulating cell-free DNA is considered to be a molecule with clinical applications (diagnosis, prognosis, monitoring of treatment responses, or patient follow-up) in...
TL;DR: Wang et al. as discussed by the authors showed that TDRG1 acted as a miR-214-5p sponge to up-regulate CLIC4 expression and promoted cell proliferation, migration, and invasion.
Abstract: Accumulated studies have revealed the critical role of long non-coding RNAs (lncRNAs) in the carcinogenesis and progression of various cancers. LncRNA TDRG1 has been reported to exhibit oncogenic potential in some cancers. However, its underlying mechanism regulating breast cancer (BC) remains obscure. QRT-PCR was used to measure the relative expression of mRNAs, and western blot was used to detect protein expression levels. CCK8 and CFSE assays were utilized to testify cell proliferation ability. Flow cytometry assay was used for cell apoptosis ability investigation. Transwell and tube formation assays were implemented to test cell migrating and invasive abilities. Relevant mechanism experiments were implemented to determine the molecular mechanism. TDRG1 was remarkably overexpressed in BC cell lines. TDRG1 knockdown suppressed cell proliferation, migration and invasion, but enhanced BC cell apoptosis. Mechanistically, TDRG1 acted as a miR-214-5p sponge to up-regulate CLIC4 expression. MiR-214-5p inhibition or CLIC4 overexpression could revive the tumor-suppressing effects induced by TDRG1 knockdown. TDRG1 promoted cell proliferation, migration, and invasion in BC, suggesting that TDRG1 could promisingly be a therapeutic target for BC.
TL;DR: In this article, a decitabine-based epigenetic therapy was used to suppress tumor growth by targeting the FBW7/Mcl-1 signaling pathway in lung cancer.
Abstract: Methylation induces epigenetic silencing of tumor suppressor genes in human lung cancer. Inhibition of DNA methyltransferases by decitabine (DAC) can demethylate and activate epigenetically silenced tumor suppressor genes. Epigenetic therapy using DAC should be an attractive strategy for lung cancer therapy. FBW7 is a tumor suppressor that functions as an Mcl-1 E3 ligase to degrade Mcl-1 by ubiquitination. Here we discovered that treatment of various human lung cancer cells with DAC resulted in activation of FBW7 expression, decreased levels of Mcl-1 protein, and growth inhibition. DAC-activated FBW7 expression promoted Mcl-1 ubiquitination and degradation leading to a significant reduction in the half-life of Mcl-1 protein. Mechanistically, treatment of lung cancer cells or lung cancer xenografts with DAC induced the conversion of the FBW7 gene from a methylated form to an unmethylated form, which was associated with the increased expression of FBW7 and decreased expression of Mcl-1 in vitro and in vivo. DAC suppressed lung cancer growth in a dose-dependent manner in vivo. Combined treatment with DAC and a Bcl2 inhibitor, venetoclax, exhibited strong synergistic potency against lung cancer without normal tissue toxicity. These findings uncover a novel mechanism by which DAC suppresses tumor growth by targeting the FBW7/Mcl-1 signaling pathway. Combination of DAC with Bcl2 inhibitor venetoclax provides more effective epigenetic therapy for lung cancer.
TL;DR: In this paper, the authors showed that exosomes, which are loaded with various biomolecules including nucleic acids, lipids, and proteins are involved in the recurrence and metastasis of hepatocellular carcinoma (HCC), a malignant tumor, is poor.
Abstract: The prognosis of hepatocellular carcinoma (HCC), a malignant tumor, is poor. Tumor recurrence and metastasis are the major challenges for the treatment of HCC. Various studies have demonstrated that exosomes, which are loaded with various biomolecules including nucleic acids, lipids, and proteins are involved in the recurrence and metastasis of HCC. Additionally, exosomes mediate various biological processes, such as immune response, cell apoptosis, angiogenesis, thrombosis, autophagy, and intercellular signal transduction. In cancer, exosomes regulate cancer cell differentiation, development, and drug resistance. Circular RNAs, microRNAs, and proteins in the exosomes can serve as early diagnostic and prognostic markers for HCC. As exosomes are characterized by low immunogenicity and high stability in the tissues and circulation, they can be used to deliver the drugs in cancer therapies.
TL;DR: Ibrutinib (Imbruvica® 2013) is a Bruton's tyrosine kinase (BTK) inhibitor approved for multiple B-cell malignancies and cGVHD.
Abstract: Ibrutinib (Imbruvica®, 2013) is a Bruton's tyrosine kinase (BTK) inhibitor approved for multiple B-cell malignancies and cGVHD. Its treatment is associated with increased risk of cardiac adverse events. Atrial fibrillation is a common cause of therapy discontinuation and interruptions, which have been correlated with shorter progression-free survival in chronic lymphocyte leukemia (CLL) patients. Recently, Xiao et al. identified that ibrutinib-mediated atrial fibrillation is likely due to off-target CSK inhibition. Given promising in vitro and in vivo evidence of maintained biological activity in CLL at lower-than-labeled ibrutinib doses, this elucidated mechanism substantiates the case to investigate alternative dosing schedules. The potential to minimize ibrutinib's off-target effects while conserving response warrants further discussion and investigation of optimal ibrutinib dosing.
TL;DR: The in vivo study of mice implanted with pancreatic tumor cells AsPC-1 demonstrates accumulation of phosphorothioate-modified Ap52 (ThioAp52) at the xenograft tumor following either intravenous or in situ injection, indicating that this aptamer against shared tumor-specific antigen can be a potential delivery vehicle for therapeutics to treat multiple cancers.
Abstract: We developed a DNA aptamer, Ap52, against the shared tumor-specific MAGE-A3111-125 peptide antigen that was used to target multiple types of cancer cells. Here we report the in vivo study of mice implanted with pancreatic tumor cells AsPC-1, which demonstrates accumulation of phosphorothioate-modified Ap52 (ThioAp52) at the xenograft tumor following either intravenous or in situ injection. When complexed with antitumor drug doxorubicin (Dox), ThioAp52 achieves targeted delivery to four types of cancer cells, including breast, oral, pancreatic, and skin. Image analysis shows that ThioAp52-Dox complex selectively enters cancer cells, while free Dox is taken up by all cell lines. The cytotoxicity of ThioAp52-Dox for cancer cells is enhanced as compared to that for the corresponding normal/noncancerous cells. These results indicate that this aptamer against shared tumor-specific antigen can be a potential delivery vehicle for therapeutics to treat multiple cancers.
TL;DR: In this paper, a combination of ONC201 and TRAIL was shown to increase the cell death in endometrial cancer patients in a Phase I clinical trial, and the results suggest a novel cancer therapeutic strategy that can be further investigated in the clinic.
Abstract: ONC201 demonstrated promising activity in patients with advanced endometrial cancer in a Phase I clinical trial. ONC201 activates the integrated stress response (ISR) and upregulates TRAIL and its receptor DR5. We hypothesized ONC201 upregulation of DR5 could sensitize tumors to TRAIL and combination of ONC201 and TRAIL would lead to enhanced cell death in endometrial cancer models. Five endometrial cancer cell lines AN3CA, HEC1A, Ishikawa, RL952, and KLE as well as a murine xenograft model were treated with ONC201 alone or in combination with TRAIL. ONC201 decreased the cell viability of all five endometrial cancer cell lines at clinically achievable low micro-molar concentrations (2-4 μM). ONC201 activated the ISR and induced protein expression of TRAIL and DR5 at the cell surface. Pretreatment with ONC201 sensitized endometrial cancer cell lines to TRAIL, leading to increased cell death induction compared to either agent alone. Tumor growth was reduced in vivo by the ONC201/TRAIL combination treatment in the xenograft model of endometrial cancer (p = .014). Mice treated with combination treatment survived significantly longer than mice from the three control groups (p = .018). ONC201 decreased cell viability in endometrial cancer cells lines primarily through growth arrest while the combination of ONC201 and TRAIL promoted cell death in vitro and in vivo. Our results suggest a novel cancer therapeutic strategy that can be further investigated in the clinic.
TL;DR: In this article, a case of an 11-year-old girl with an inoperable tumor in the optic chiasm/hypothalamus, who experienced several tumor progressions despite three lines of chemotherapy treatment was reported.
Abstract: Here we report a case of an 11-year-old girl with an inoperable tumor in the optic chiasm/hypothalamus, who experienced several tumor progressions despite three lines of chemotherapy treatment. Routine clinical examination classified the tumor as a BRAF-negative pilocytic astrocytoma. Copy-number variation profiling of fresh frozen tumor material identified two duplications in 9q21.32-33 leading to breakpoints within the GKAP1 and NTRK2 genes. RT-PCR Sanger sequencing revealed a GKAP1-NTRK2 exon 10-16 in-frame fusion, generating a putative fusion protein of 658 amino acids with a retained tyrosine kinase (TK) domain. Functional analysis by transient transfection of HEK293 cells showed the GKAP1-NTRK2 fusion protein to be activated through phosphorylation of the TK domain (Tyr705). Subsequently, downstream mediators of the MAPK- and PI3K-signaling pathways were upregulated in GKAP1-NTRK2 cells compared to NTRK2 wild-type; phosphorylated (p)ERK (3.6-fold), pAKT (1.8- fold), and pS6 ribosomal protein (1.4-fold). Following these findings, the patient was enrolled in a clinical trial and treated with the specific TRK-inhibitor larotrectinib, resulting in the arrest of tumor growth. The patient's condition is currently stable and the quality of life has improved significantly. Our findings highlight the value of comprehensive clinical molecular screening of BRAF-negative pediatric low-grade gliomas, to reveal rare fusions serving as targets for precision therapy.
TL;DR: Wang et al. as discussed by the authors found that LINC00284 sponged microRNA 211-3p to upregulate MAF bZIP transcription factor G (MAFG) expression in OSCC cells.
Abstract: Oral squamous cell carcinoma (OSCC) is one of the most common malignancies worldwide. Emerging evidence has suggested that long noncoding RNAs (lncRNAs) play vital roles in various biological processes of cancers, such as cell proliferation, migration, invasion, and apoptosis. As reported previously, long intergenic non-protein coding RNA 284 (LINC00284) is an important regulator in multiple cancers. However, the biological role, as well as regulatory mechanism of LINC00284 in OSCC, has not been investigated. In our study, RT-qPCR results indicated that LINC00284 was significantly upregulated in OSCC tissues and cells. Moreover, loss-of-function experiments demonstrated that LINC00284 downregulation suppressed cell proliferation and migration and facilitated cell apoptosis. Mechanistically, we found that LINC00284 sponged microRNA 211-3p (miR-211-3p) to upregulate MAF bZIP transcription factor G (MAFG) expression in OSCC cells. Additionally, LINC00284 interacted with FUS protein to increase KAZN mRNA stability. Functional assays showed that either MAFG or KAZN overexpression promoted the malignant behaviors of OSCC cells. Through a series of rescue assays, we found that the inhibitory effect of silencing LINC00284 on OSCC cells can be reversed by upregulated MAFG and KAZN. Overall, silencing LINC00284 inhibits the malignant characteristics of OSCC cells by downregulating MAFG and inhibiting the binding of FUS to KAZN mRNA.
TL;DR: In this article, a short review discusses recent progress in the inhibition of NF-κB activation by proteasome inhibitors, which prevents the degradation of protein IκB, which accumulates in the cytosol, and there by the activation of NFκB.
Abstract: The Ubiquitin-Proteasome System plays a central role in signal transduction associated with stress, in the skin in particular by the control of NF-κB pathways. Under normal conditions, the inhibitory protein IκB is phosphorylated by kinases, then ubiquitinated and ends up at the proteasome to be degraded. The present short review discusses recent progress in the inhibition of NF-κB activation by proteasome inhibitors prevents the degradation of protein IκB, which accumulates in the cytosol, and there by the activation of NF-κB. Moreover, would not only limit the expression of adhesion molecules and cytokines involved in metastatic processes, but also increase the sensitivity of cancer cells to apoptosis. Considering this fact, the activity of NF-κB is regulated by the phosphorylation and proteasome-dependent degradation of its inhibitor Iκb. In this scenario, the use of a proteasome inhibitor might be an effective strategy in the treatment of skin cancer with constitutive activation of NF-κB.
TL;DR: It was found that MAP17 could inhibit cell apoptosis by suppressing the activation of the p38 pathway, and that miR-27a-3p reversed the effects of MAP17 in A549 cells by directly targeting MAP17.
Abstract: The overexpression of MAP17 has been reported in various human carcinomas. However, its molecular mechanism in non-small cell lung cancer (NSCLC) has not been fully understood. Our study aimed to r...
TL;DR: In this article, the authors investigated the specific role of circ_C20orf11 in regulating chemoresistance to cisplatin (DDP)in ovarian cancer and found that the effect of circ20f11 on specific cellular characteristics (proliferation, apoptosis, DDP resistance) via a series of experiments.
Abstract: Ovarian cancer is a fatal gynecologic tumor, and conventional treatment is mainly limited by chemoresistance. The mechanism contributing to chemoresistance in ovarian cancer has yet to be established. This study aimed to investigate the specific role of circ_C20orf11 in regulating chemoresistance to cisplatin (DDP)in ovarian cancer. We first established two DDP-resistant ovarian cancer cell lines. Then, we identified the effect of circ_C20orf11 on specific cellular characteristics (proliferation, apoptosis, DDP resistance) via a series of experiments. The binding sites between circ_C20orf11 and miR-527 and between miR-527 and YWHAZ were predicted using a bioinformatics tool and confirmed with a dual-luciferase reporter assay. Furthermore, extracellular vesicles (EVs) derived from DDP-resistant cell lines were identified, and the effect of EVs on macrophage polarization was examined. circ_C20orf11 was upregulated in ovarian cancer. Increased circ_C20orf11 expression enhanced DDP resistance and cell proliferation and reduced cell apoptosis in DDP-resistant cell lines after DDP treatment by sponging miR-527 and promoting YWHAZ expression. In addition, we found that DDP-resistant cell-derived EVs can induce macrophage M2 polarization, whereas silencing of circ_C20orf11 inhibited EV-induced macrophage M2 polarization. Consistent with these results, silencing of circ_C20orf11 enhanced sensitivity to DDP in vivo. Importantly, we proved that circ_C20orf11 expression was upregulated in EVs extracted from the serum of DDP-resistant patients. Our study demonstrated that silencing circ_C20orf11 sensitizes ovarian cancer to DDP by promoting miR-527/YWHAZ signaling and EV-mediated macrophage M2 polarization.
TL;DR: Initial evidence is provided that targeting EZH2 is a promising therapeutic strategy for the treatment of subtypes of pediatric AML by demonstrating a significant increase in apoptosis in cells treated with drug combination (EZH 2i and selinexor) compared to EZh2i inhibitors alone.
Abstract: Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and a catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the mono-, di-, and tri-methylation of histone H3 at Lys 27 (H3K27me3) to facilitate chromatin-remodeling and gene-silencing functions. Previous reports showed a significant association of EZH2 aberrations in pediatric cancers, such as soft tissue sarcomas and glioblastoma. Recent reports in human subjects and animal models have also suggested a central role of EZH2 in the induction and progression of acute myeloid leukemia. In this study, we aimed to investigate the molecular status of EZH in cell lines derived from distinct pediatric leukemia to assess the efficacy of targeting EZH2 to suppress cancer cell survival and proliferation. Our results showed that EZH2 protein is overexpressed in the pediatric monocytic cell-line THP-1, but not in other leukemia-derived cell lines MV4;11 and SEM. Screening a panel of methyltransferase inhibitors revealed that three inhibitors; GSK126, UNC1999 and EPZ-5687 are the most potent inhibitors that suppressed EZH2 activity selectively on lysine 27 which resulted in increased apoptosis and inhibition of AKT and ERK protein phosphorylation in THP-1 cells. Our data demonstrated a significant increase in apoptosis in cells treated with drug combination (EZH2i and selinexor) compared to EZH2i inhibitors alone. Taken together, our data provide initial evidence that targeting EZH2 is a promising therapeutic strategy for the treatment of subtypes of pediatric AML. Also, combining EZH2 inhibitors with selinexor may increase the treatment efficacy in these patients.
TL;DR: In this paper, the authors performed a retrospective cohort analysis of a comprehensively annotated cohort of 561 patients at a National Cancer Institute-designated comprehensive cancer center with advanced solid cancers who underwent ctDNA testing using a commercial targeted next-generation sequencing assay.
Abstract: Circulating tumor DNA (ctDNA) is utilized for molecular profiling of cancers, and is under investigation for a growing number of applications based on the assumption that ctDNA levels faithfully reflect disease burden. Our objective was to investigate whether patient and tumor characteristics may impact ctDNA detection or levels and the prognostic significance of ctDNA levels or mutations. We performed a retrospective cohort analysis of a comprehensively annotated cohort of 561 patients at a National Cancer Institute-designated comprehensive cancer center with advanced solid cancers who underwent ctDNA testing using a commercial targeted next-generation sequencing assay. ctDNA detection in advanced cancers was associated with older age, non-obese body mass index, and diabetes, but not with tumor diameter, volume, lesion number, or other pathological features. Regression models indicate that no more than 14.3% of the variance in ctDNA levels between patients was explained by known clinical factors and disease burden. Even after adjusting for established prognostic factors and tumor burden, ctDNA levels were associated with worse survival among patients without prior systemic therapy, while ctDNA mutations were associated with survival among patients who previously received systemic treatment. These findings uncover clinical factors that affect ctDNA detection in patients with advanced cancers and challenge the convention that ctDNA is a surrogate for tumor burden. Our study also indicates that the prognostic value of ctDNA levels and mutations are independent of tumor burden and dependent on treatment context.
TL;DR: In this paper, a review aims at recent advancements in the identification and characterization of new biomarkers, microRNAs, which might prove useful in the early detection of pancreatic ductal adenocarcinoma (PDAC).
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, with poor prognosis resulting mostly from late diagnosis. Surgery remains the most effective treatment and early detection significantly increases the overall survival. Biomarkers used for diagnosis and to monitor the response to treatment, such as carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA), are not adequate as early detection markers of PDAC, partly due to low sensitivity/specificity. Therefore, new biomarkers for PDAC are critically needed. This review aims at recent advancements in the identification and characterization of new biomarkers, microRNAs, which might prove useful in the early detection of PDAC.