More and more evidence indicates that circular RNAs (circRNAs) have important roles in several diseases, especially in cancers. However, their involvement remains to be investigated in breast cancer. Through screening circRNA profile, we identified 235 differentially expressed circRNAs in breast cancer. Subsequently, we explored the clinical significance of two circTADA2As in a large cohort of triple-negative breast cancer (TNBC), and performed functional analysis of circTADA2A-E6 in vitro and in vivo to support clinical findings. Finally, we evaluated the effect of circTADA2A-E6 on miR-203a-3p and its target gene SOCS3. We detected two circRNAs, circTADA2A-E6 and circTADA2A-E5/E6, which were among the top five differentially expressed circRNAs in breast cancer. They were consistently and significantly decreased in a large cohort of breast cancer patients, and their downregulation was associated with poor patient survival for TNBC. Especially, circTADA2A-E6 suppressed in vitro cell proliferation, migration, invasion, and clonogenicity and possessed tumor-suppressor capability. circTADA2A-E6 preferentially acted as a miR-203a-3p sponge to restore the expression of miRNA target gene SOCS3, resulting in a less aggressive oncogenic phenotype. circTADA2As as promising prognostic biomarkers in TNBC patients, and therapeutic targeting of circTADA2As/miRNA/mRNA network may be a potential strategy for the treatment of breast cancer.

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circTADA2As suppress breast cancer progression and metastasis via targeting miR-203a-3p/SOCS3 axis.

circRNA-miRNA-mRNA in breast cancer

Cancer incidence rate has been increasing drastically in recent years. One of the many cancer treatment methods is chemotherapy. Traditional medicine, in the form of complementary and alternative therapy, is actively used to treat cancer, and many herbs and active ingredients of such therapies are being intensely studied to integrate them into modern medicine. Ginseng is traditionally used as a nourishing tonic and for treating various diseases in Asian countries. The therapeutic potential of ginseng in modern medicine has been studied extensively; the main bioactive component of ginseng is ginsenosides, which have gathered attention, particularly for their prospects in the treatment of fatal diseases such as cancer. Ginsenosides displayed their anticancer and antimetastatic properties not only via restricting cancer cell proliferation, viability, invasion, and migration but also by promoting apoptosis, cell cycle arrest, and autophagy in several cancers, such as breast, brain, liver, gastric, and lung cancer. Additionally, ginsenosides can work synergistically with already existing cancer therapies. Thus, ginsenosides may be used alone or in combination with other pharmaceutical agents in new therapeutic strategies for cancer. To date however, there is little systematic summary available for the anticancer effects and therapeutic potential of ginsenosides. Therefore, we have reviewed and discussed all available literature in order to facilitate further research of ginsenosides in this manuscript.

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Anticancer Activities of Ginsenosides, the Main Active Components of Ginseng.

Epstein-Barr virus (EBV) is closely associated with multiple human cancers. EBV-associated cancers are mainly lymphomas derived from B cells and T cells (Hodgkin lymphoma, Burkitt lymphoma, NK/T-cell lymphoma, and posttransplant lymphoproliferative disorder (PTLD)) and carcinomas derived from epithelial cells (nasopharyngeal carcinoma and gastric carcinoma). EBV can induce oncogenesis in its host cell by activating various signaling pathways, such as nuclear factor-κB (NF-κB), phosphoinositide-3-kinase/protein kinase B (PI3K/AKT), Janus kinase/signal transducer and transcription activator (JAK/STAT), mitogen-activated protein kinase (MAPK), transforming growth factor-β (TGF-β), and Wnt/β-catenin, which are regulated by EBV-encoded proteins and noncoding RNA. In this review, we focus on the oncogenic roles of EBV that are mediated through the aforementioned signaling pathways.

/pdf/signaling-pathways-of-ebv-induced-oncogenesis-1mh9eldi0k.pdf

Signaling pathways of EBV-induced oncogenesis

Circular RNAs (circRNAs) are a class of endogenous single-strand RNA transcripts with crucial regulation in human cancers. The objective of this study is to investigate the role of circ_0082182 in CRC and its specific functional mechanism. The quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure the levels of circ_0082182, microRNA-411 (miR-411) and microRNA-1205 (miR-1205). Cell proliferation was detected by Cell counting Kit-8 (CCK-8) and colony formation assays. Flow cytometry was used for determining cell cycle and cell apoptosis. Cell apoptosis was also assessed by caspase3 and caspase9 activities. Cell migration and invasion were examined using scratch assay and transwell assay. The interaction between circ_0082182 and miRNA was validated by the dual-luciferase reporter and biotinylated RNA pull-down assays. Wnt/β-catenin pathway and epithelial-mesenchymal transition (EMT)-associated proteins were quantified by Western blot. Xenograft model was established for the research of circ_0082182 in vivo. Circ_0082182 was upregulated in CRC and could predict the poor prognosis of CRC patients. Functionally, circ_0082182 promoted CRC cell proliferation, cell cycle progression, and metastasis while inhibited apoptosis. Subsequently, circ_0082182 was shown to act as the sponges of miR-411 and miR-1205. MiR-411 and miR-1205 were identified as tumor inhibitors in CRC. Furthermore, circ_0082182 promoted the CRC progression via sponging miR-411 and miR-1205. Moreover, circ_0082182 facilitated the Wnt/β-catenin pathway and EMT process by targeting miR-411 and miR-1205. In vivo, circ_0082182 accelerated the CRC tumorigenesis and EMT process by activating the Wnt/β-catenin pathway by downregulating the expression of miR-411 or miR-1205. This study showed that circ_0082182 functioned as an oncogene in the developing process of CRC by sponging miR-411 or miR-1205 to activate the Wnt/β-catenin pathway. Circ_0082182 might be a molecular target in the diagnosis and treatment of CRC.

/pdf/circ-0082182-promotes-oncogenesis-and-metastasis-of-4xk6694ivj.pdf

Circ_0082182 promotes oncogenesis and metastasis of colorectal cancer in vitro and in vivo by sponging miR-411 and miR-1205 to activate the Wnt/β-catenin pathway.

Gastric cancer is one of the most common gastrointestinal tumor types, and the incidence and mortality rates are higher in men compared with women. Various studies have revealed that gastric cancer is a spectrum of tumor types, which have biological and genetic diversity. It has proven to be difficult to improve the overall survival and disease-free survival of patients with gastric cancer through the use of traditional surgery and chemoradiation, as gastric cancer is usually identified at an advanced stage. In consequence, the outcome is frequently poor. Thus, novel biomarkers and anticancer targets are required to improve the outcome. As the identification of biomarkers has increased due to advances in research and the greater availability of bioinformatics and functional genomics, the potential therapeutic regimens available have also increased concurrently. These advances have also improved the ability to predict responses to chemotherapy, targeted therapy and immunotherapy, whilst other biomarkers predict post-treatment survival and recurrence based on their expression. This review focuses closely on the important functions of biomarkers in the timely diagnosis and treatment of gastric cancer, in addition to the advances in the study of certain novel markers in gastric cancer.

/pdf/significant-function-and-research-progress-of-biomarkers-in-22qa3uo20i.pdf

Significant function and research progress of biomarkers in gastric cancer.

Background: Circular RNAs (circRNAs) have been reported to play important roles in cancer progression. However, the potential involvement of circRNAs in breast cancer metastasis to the lung remains unclear. Methods: High-throughput circular RNA microarray assays of primary breast cancer tissues and lung metastatic tissues were performed. Reactome pathway analysis and GO analysis of the linear mRNA transcripts corresponding to the circRNAs were conducted. The expression of the top downregulated circRNA was confirmed by qRT-PCR in breast cancer cell lines. Kaplan-Meier survival analysis was conducted to analyze the clinical significance of the selected circRNA in breast cancer. A series of in vitro and in vivo experiments, including cell proliferation and migration, was performed to explore the functions of the selected circRNA in breast cancer progression. We further investigated the regulatory effect of the selected circRNA on a miRNA and its target genes to explore the potential mechanisms. Results: We found that circNFIC (hsa_circ_0002018) was the most downregulated circRNA in lung metastatic tissues. Kaplan-Meier survival analysis revealed that low levels of circNFIC were related to poor outcome of breast cancer. Further experiments revealed that overexpressing circNFIC suppressed breast cancer cell proliferation and migration to the lung. A mechanistic study showed that circNFIC acted as a sponge for miR-658 and competed for binding to miR-658 with UPK1A, leading to increased expression of UPK1A. Conclusion: Our study highlighted the regulatory function of the circNFIC/miR-658/UPK1A pathway in breast cancer progression, which could be a potential therapeutic target for breast cancer.

/pdf/circnfic-suppresses-breast-cancer-progression-by-sponging-54qida66bg.pdf

circNFIC suppresses breast cancer progression by sponging miR-658.

Background: Latent membrane protein 1 (LMP1) is known as an oncogenic protein encoded by the EBV genome. The purpose of this study was to investigate the mechanism of LMP1-induced cell epithelial-mesenchymal transition (EMT). Methods: The NP69 cell line of nasopharyngeal epithelial cells with high expression of LMP1 was established to observe the effect of high expression of LMP1 on cell growth, proliferation, cycle, apoptosis, migration and invasion. We used proteomics to screen and identify differentially expressed proteins related to LMP1-mediated epithelial cell transformation. Then, we analyzed the expression and significance of differentially expressed calreticulin (CRT) in nasopharyngeal carcinoma (NPC), and observed the effect of CRT expression on EMT in CNE2 cells of NPC. Finally, the expression of neuropilin-1 (NRP1), which is a protein downstream of the EMT-related signaling pathway TGF-β (transforming growth factor β), was detected. Results: LMP1 promoted NP69 cells proliferation, inhibited apoptosis and induced EMT. We identified 22 differentially expressed proteins associated with LMP1-induced EMT. Among them, CRT expression level was significantly increased in NPC compared with adjacent tissues, and was interrelated with TNM staging and lymph node metastasis of NPC. After knockdown of CRT expression, the phenomenon of cell EMT was reduced and the ability of cell migration and invasion was weakened. CRT regulated NRP1 expression by affecting SMAD3 phosphorylation. Conclusion: LMP1 induced cell EMT via TGF-β/Smad3/NRP1 pathway, which promoted migration and invasion of NPC cells.

/pdf/lmp1-up-regulates-calreticulin-to-induce-epithelial-yqbmqiwbob.pdf

LMP1 Up-regulates Calreticulin to Induce Epithelial-mesenchymal Transition via TGF-β/Smad3/NRP1 Pathway in Nasopharyngeal Carcinoma Cells.

Objective: Gastric cancer is one of the most common malignant tumors in the world. IGHG1 is a differentially expressed protein screened out in gastric cancer in the early stage of the subject group. This topic explores the expression of IGHG1 in gastric cancer and the effect of IGHG1 on the proliferation, migration, invasion and EMT of gastric cancer SGC7901 cells and its mechanism of action. Methods: Twenty cases of gastric cancer were purified by laser Capture Microdissection. The isotopic tags for relative and absolute quantification was used to label the proteins, and then analyzed and identified them by quantitative proteomics. Immunohistochemical staining method was used to detect the expression of IGHG1 protein in gastric cancer tissues. Western blot was used to detect the expression of IGHG1 in gastric cancer cells. The MTT and Petri dish clone formation experiment analyzed the effect of low expression of IGHG1 on the proliferation of SGC7901 cells. Scratch test and Transwell migration and invasion test to observe the effect of low expression of IGHG1 on the migration and invasion of SGC7901 cells. Western blot was used to detect the effect of low expression of IGHG1 on the expression of EMT-related proteins. Results: 243 proteins related to gastric mucosal lesions were preliminarily identified. We found that IGHG1 is highly expressed in gastric cancer tissues compared with normal control tissues. IGHG1 promotes the proliferation, migration and invasion of gastric cancer cells. Compared with the control group, the expression of EMT-related proteins Vimentin, N-cadherin, TGF-β, P-SMAD3 was decreased and the expression of E-cadherin was increased after IGHG1 low expression. Conclusions: IGHG1 induces EMT in SGC7901 cells by regulating the TGF-β/SMAD3 signaling pathway.

/pdf/ighg1-induces-emt-in-gastric-cancer-cells-by-regulating-tgf-19ogtvlm2c.pdf

IGHG1 induces EMT in gastric cancer cells by regulating TGF-β/SMAD3 signaling pathway.

Circular RNAs (circRNAs) is one type of non-coding RNAs (ncRNAs) which have many roles in biological processes, as well as modulation intracellular gene expression modulation. Nonethless, the roles along with expression status of the most circRNAs in NSCLC (non-small cell lung cancer) remain unknown. Herein, we conducted a high-throughput microarray sequencing to identify abnormal expressed circRNAs. Circ0101675 was found upregulated in NSCLC cell lines and tissues. We carried out colony formation, transwell, CCK-8, and animal assays to investigate the functions of circ0101675. Silence of circ0101675 inhibited the migration and proliferation of NSCLC. To elucidate the mechanism, RNA immunoprecipitation assays along with luciferase enzyme reporter assays were further employed to explore the cross-talk between circ0101675 and other molecules. We discovered that circ0101675 facilitates the malignant process of growth and migration via sponging miR-1278 and upregulating WNT3A/5A expression. In conclusion, we revelaed the vital role of circ0101675-miR-1278-WNT3A/5A signaling in NSCLC progression via the competing endogenous RNAs mechanism. Therefore, circ0101675 can be used as a new and useful biomarker for monitoring and treating NSCLC.

/pdf/circ0101675-promotes-malignant-process-via-sponging-mir-1278-506f20g3nt.pdf

Zhiwei Zhang

Papers

Significant function and research progress of biomarkers in gastric cancer.

circNFIC suppresses breast cancer progression by sponging miR-658.

LMP1 Up-regulates Calreticulin to Induce Epithelial-mesenchymal Transition via TGF-β/Smad3/NRP1 Pathway in Nasopharyngeal Carcinoma Cells.

IGHG1 induces EMT in gastric cancer cells by regulating TGF-β/SMAD3 signaling pathway.

circ0101675 promotes malignant process via sponging miR-1278 and upregulating WNT3A/5A in non-small cell lung cancer.