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Targeted therapy has been established as a therapeutic option for the treatment of metastatic melanoma. Despite initially being very efficient, many tumors develop resistance to targeted therapy, leading to its failure. We previously demonstrated that the neural crest (NC)-associated gene ERRFI1 is highly expressed in metastatic melanoma and correlates with a bad prognosis. Here, we show that the expression of ERRFI1 was upregulated in melanoma and negatively correlated with the expression of melanocytic differentiation markers, such as MITF and TYR. Downregulation of ERRFI1 with the help of siRNA increased the susceptibility of melanoma cells toward BRAF inhibition (BRAFi) and resensitized BRAFi-resistant melanoma cells to BRAFi. Mass spectrometry-based proteomic analysis revealed that ERRFI1 silencing diminished the activation of the mitogen-activated protein kinase (MAPK) and AKT signaling pathways, which usually contribute to drug resistance. Furthermore, we show that miR-200c targeted the 3'UTR of ERRFI1 and reduced its expression, resulting in the resensitization of BRAFi-resistant melanoma cells to BRAFi. Our study results suggest that ERRFI1 could be a potential therapeutic target for the treatment of metastatic melanoma.

Background Hypoxia is a key feature of breast cancer, which affects cancer development, metastasis and metabolism. Previous studies suggested that circular RNAs (circRNAs) could participate in cancer progression and hypoxia regulation. This study aimed to investigate the role of circRNA differentially expressed in normal cells and neoplasia domain containing 4C (circDENND4C) in breast cancer progression under hypoxia. Methods Forty-three patients with breast cancer were involved in this study. Breast cancer cell lines MDA-MB-453 and SK-BR-3 were cultured under hypoxia (1% O 2 ) for experiments in vitro. The expression levels of circDENND4C, microRNA-200b (miR-200b) and miR-200c were measured by quantitative real-time polymerase chain reaction. Glycolysis was investigated by glucose consumption, lactate production and hexokinase II (HK2) protein level. Migration and invasion were evaluated via trans-well assay and protein levels of matrix metallopeptidase 9 (MMP9) and MMP2. The interaction between circDENND4C and miR-200b or miR-200c was explored by bioinformatics analysis, luciferase assay and RNA immunoprecipitation. Murine xenograft model was established to investigate the anti-cancer role of circDENND4C in vivo. Results circDENND4C highly expressed in breast cancer was up-regulated in response to hypoxia. Knockdown of circDENND4C decreased glycolysis, migration and invasion in breast cancer cells under hypoxia. circDENND4C was validated as a sponge of miR-200b and miR-200c. Deficiency of miR-200b or miR-200c reversed the suppressive effect of circDENND4C knockdown on breast cancer progression. Moreover, silence of circDENND4C reduced xenograft tumor growth by increasing miR-200b and miR-200c. Conclusion circDENND4C silence suppresses glycolysis, migration and invasion in breast cancer cells under hypoxia by increasing miR-200b and miR-200c.

Objective Distant metastasis is the major cause of cancer-related death in patients with colorectal cancer (CRC). Although the microRNA-200 (miR-200) family is a crucial inhibitor of epithelial-to-mesenchymal transition (EMT) in human cancer, the role of miR-200 members in the pathogenesis of metastatic CRC has not been investigated. Design Fifty-four pairs of primary CRC and corresponding matched liver metastasis tissue specimens were analysed for expression and methylation status of the miR-200 family members. Functional analysis of miR-200c overexpression was investigated in CRC cell lines, and cells were analysed for proliferation, invasion and migration. Expression of several miR-200c target genes (ZEB1, ETS1 and FLT1) and EMT markers (E-cadherin and vimentin) in CRC cell lines and tissue specimens was validated. Results Liver metastasis tissues showed higher expression of miR-200c (primary CRC=1.31 vs. liver metastasis=1.59; p=0.0014) and miR-141 (primary CRC=0.14 vs. liver metastasis=0.17; p=0.0234) than did primary CRCs, which was significantly associated with hypomethylation of the promoter region of these miRNAs (primary CRC=61.2% vs. liver metastasis=46.7%; p<0.0001). The invasive front in primary CRC tissues revealed low miR-200c expression by in situ hybridization analysis. Transfection of miR-200c precursors resulted in enhanced cell proliferation but reduced invasion and migration behaviours in CRC cell lines. Overexpression of miR-200c in CRC cell lines caused reduced expression of putative gene targets, and resulted in increased E-cadherin and reduced vimentin expression. The associations between miR-200c, target genes and EMT markers were validated in primary CRCs and matching liver metastasis tissues. Conclusions miR-200c plays an important role in mediating EMT and metastatic behaviour in the colon. Its expression is epigenetically regulated, and miR-200c may serve as a potential diagnostic marker and therapeutic target for patients with CRC.

Background Accumulating evidence indicates that long non-coding RNAs (lncRNAs) are potential biomarkers and key regulators of tumour development and progression. SOX2 overlapping transcript (SOX2OT) is a novel lncRNA that acts as a potential biomarker and is involved in the development of cancer and cancer stem cells. However, the clinical significance and molecular mechanism of SOX2OT in bladder cancer are still unknown. Methods The expression level of SOX2OT was determined by RT-qPCR in a total of 106 patients with urothelial bladder cancer and in different bladder cancer cell (BCC) lines. Bladder cancer stem cells (BCSCs) were isolated from BCCs using flow cytometry based on the stem cell markers CD44 and ALDH1. Loss-of-function experiments were performed to investigate the biological roles of SOX2OT in the stemness phenotype of BCSCs. Comprehensive transcriptional analysis, RNA FISH, dual-luciferase reporter assays and western blots were performed to explore the molecular mechanisms underlying the functions of SOX2OT. Results SOX2OT was highly expressed in bladder cancer, and increased SOX2OT expression was positively correlated with a high histological grade, advanced TNM stage and poor prognosis. Further experiments demonstrated that knockdown of SOX2OT inhibited the stemness phenotype of BCSCs. Moreover, inhibition of SOX2OT delayed xenograft tumour growth and decreased metastases in vivo. Mechanistically, we found that SOX2OT was mainly distributed in the cytoplasm and positively regulated SOX2 expression by sponging miR-200c. Furthermore, SOX2 overexpression reversed the SOX2OT silencing-induced inhibition of the BCSC stemness phenotype. Conclusion This study is the first to demonstrate that SOX2OT plays an important regulatory role in BCSCs and that SOX2OT may serve as a potential diagnostic biomarker and therapeutic target in bladder cancer.

Background The abnormal expression of non-coding RNAs (ncRNAs), such as microRNAs and long ncRNAs, often contribute to the development of cancers. miR-200c functions as a tumour suppressor that impacts the growth of bladder cancer cells and the epithelial-to-mesenchymal transition (EMT). LncRNA X inactive specific transcript (XIST) is highly expressed in tumour tissues, promotes cancer progression and might act as an miRNA molecular sponge. This study aimed to examine the relationship between lncRNA XIST and miR-200c and to assess their functions in the regulation of the stemness properties and tumourigenicity of human bladder cancer stem cell (BCSC)-like cells. Methods Biological effects including cell clone formation, sphere formation, self-renewal properties and mouse tumourigenesis were examined in BCSC-like cells with miR-200c overexpression or XIST knockdown. Real-time PCR and western blotting were used to detect the expression changing of related factors in BCSC-like cells gene models. Dual luciferase reporter assay was used to examine the changes of XIST and miR-200c expression levels. Results The results indicated that miR-200c overexpression and XIST knockdown could inhibit cell clone formation, self-renewal ability and EMT in BCSC-like cells. miR-200c knockdown could restore the tumour growth inhibition caused by XIST knockdown. Conclusion LncRNA XIST may act as an inhibitor of miR-200c to regulate the stemness properties and tumourigenicity of bladder cancer cells, and our findings might reveal a potential strategy of targeting XIST for bladder cancer therapy.

Vitiligo is a refractory disfiguring skin disease. However, the aetiology and pathogenesis of vitiligo have not been fully defined. Previous studies have shown that exosomes from normal human keratinocytes improve melanogenesis by up‐regulating the expression of melanogenesis‐related proteins. Several microRNAs (miRNAs) have been demonstrated to be effective in modulating melanogenesis via exosomes. In the present study, it was found that the effect of exosomes derived from keratinocytes in vitiligo lesions in regulating melanin synthesis is weakened. Furthermore, miR‐200c was detected to be significantly down‐regulated in exosomes from keratinocytes in vitiligo lesions. In addition, miR‐200c enhanced the expression of melanogenesis‐related genes via suppressing SOX1 to activate β‐catenin. In conclusion, our study revealed that the effect of exosomes secreted by keratinocytes in vitiligo lesions exhibited a weaker capacity in promoting melanogenesis of melanocytes. Moreover, the expression of miR‐200c, which mediates melanogenesis in exosomes secreted by keratinocytes in vitiligo lesions, is down‐regulated, which may be one of the pathogenesis in vitiligo. Therefore, keratinocyte‐derived exosomal miR‐200c may be a potential target for the treatment of vitiligo.

Among the gynecological malignancies, ovarian cancer is the most fatal due to its high mortality rate. Most of the identified cases are epithelial ovarian cancer (EOC) with five distinct subtypes: high-grade serous carcinoma, low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, and clear-cell carcinoma. Lack of an early diagnostic approach, high incidence of tumor relapse and the heterogenous characteristics between each EOC subtypes contribute to the difficulties in developing precise intervention and therapy for the patients. MicroRNAs (miRNAs) are single-stranded RNAs that have been shown to function as tumor suppressors or oncomiRs. The miR-200 family, especially miR-200c, has been shown to be implicated in the metastasis and invasion of ovarian carcinoma due to its functional regulation of epithelial-to-mesenchymal transition (EMT). This mini review is aimed to summarize the recent findings of the miR-200c functional role as well as its validated targets in the metastasis cascade of ovarian cancer, with a focus on EMT regulation. The potential of this miRNA in early diagnosis and its dual expression status are also discussed.

The estrogenic receptor beta (ERβ) protects against carcinogenesis by stimulating apoptosis. Bisphenol A (BPA) is related to promoting cancer, and naringenin has chemoprotective activities both can bind to ERβ. Naringenin in the colon is metabolized by the microbiota. Cancer involves genetic and epigenetic mechanisms, including miRNAs. The objective of the present study was to evaluate the co-exposure effect of colonic in vitro fermented extract of naringenin (FEN) and BPA, to elucidate molecular effects in HT-29 colon cancer cell line. For this, we quantified genes related to the p53 signaling pathway as well as ERβ, miR-200c, and miR-141. As an important result, naringenin (IC50 250 µM) and FEN (IC50 37%) promoted intrinsic pathways of apoptosis through phosphatase and tensin homolog (PTEN) (+2.70, +1.72-fold, respectively) and CASP9 (+3.99, +2.03-fold, respectively) expression. BPA decreased the expression of PTEN (−3.46-fold) gene regulated by miR-200. We suggest that once co-exposed, cells undergo a greater stress forcing them to mediate other extrinsic apoptosis mechanisms associated with death domain FASL. In turn, these findings are related to the increase of ERβ (5.3-fold with naringenin and 13.67-fold with FEN) gene expression, important in the inhibition of carcinogenic development.

Diabetic nephropathy (DN) is one of the main complications of diabetes mellitus (DM), which leads to the long-term loss of kidney functions. Long noncoding RNAs (LncRNAs) can alleviate DN by interacting with microRNAs (miRNAs). In this work, we aimed to explore the effects of the MALAT1/miR-200c/NRF2 regulatory axis on the pyroptosis and oxidative stress (Oxidative stress, OS) of renal podocytes in high glucose (HG) environment and whether the lipid-lowering drug atorvastatin (AT) can relieve renal OS through this approach. MPC-5, a mouse podocyte cell line, was induced by HG as a cell model. The protein expressions of caspase-1, GSDMD, NLRP3, NRF2, etc. were detected by Western blotting and immunofluorescence, and the mRNA level of caspase-1, GSDMD, NLRP3, NRF2, MALAT1, miR-200c was tested by qRT-PCR. The cell pyroptosis of podocytes treated with AT was verified by CCK-8 or flow cytometry. The levels of Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were measured by spectrophotometer, respectively. The caspase-1 was upregulated in time-dependent manner and got the peak at 48 h and 30 mmol/L respectively in MPC-5 cells treated with HG. Further, the expression of GSDMD, MALAT1 and miR-200c were increased, while the level of NRF2, HO-1, OS-related indicators, were decreased simultaneously. Knockdown the MALAT1 protected MPC-5 cells from pyroptosis and OS induced by HG. However, overexpressing miR-200c in control-group cells increased pyroptosis and upregulated the OS level with HG culture medium. Further, atorvastatin protected MPC-5 cells from cell pyroptosis and downregulated the level of renal OS via attenuating the expression of MALAT1 and miR-200c. Atorvastatin protects podocyte cells via MALAT1/miR-200c/NRF2 signal pathway from pyroptosis and OS induced by HG.

Background The management of pancreatic cancer (PanCa) is exceptionally difficult due to poor response to available therapeutic modalities. Tubulins play a major role in cell dynamics, thus are important molecular targets for cancer therapy. Among various tubulins, βIII and βIV-tubulin isoforms have been primarily implicated in PanCa progression, metastasis and chemo-resistance. However, specific inhibitors of these isoforms that have potent anti-cancer activity with low toxicity are not readily available. Methods We determined anti-cancer molecular mechanisms and therapeutic efficacy of a novel small molecule inhibitor (VERU-111) using in vitro (MTS, wound healing, Boyden chamber and real-time xCELLigence assays) and in vivo (xenograft studies) models of PanCa. The effects of VERU-111 treatment on the expression of β-tubulin isoforms, apoptosis, cancer markers and microRNAs were determined by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses. Results We have identified a novel small molecule inhibitor (VERU-111), which preferentially represses clinically important, βIII and βIV tubulin isoforms via restoring the expression of miR-200c. As a result, VERU-111 efficiently inhibited tumorigenic and metastatic characteristics of PanCa cells. VERU-111 arrested the cell cycle in the G2/M phase and induced apoptosis in PanCa cell lines via modulation of cell cycle regulatory (Cdc2, Cdc25c, and Cyclin B1) and apoptosis - associated (Bax, Bad, Bcl-2, and Bcl-xl) proteins. VERU-111 treatment also inhibited tumor growth ( P  < 0.01) in a PanCa xenograft mouse model. Conclusions This study has identified an inhibitor of βIII/βIV tubulins, which appears to have excellent potential as monotherapy or in combination with conventional therapeutic regimens for PanCa treatment.