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Therapy resistance is a major clinical problem in cancer medicine and crucial for disease relapse and progression. Therefore, the clinical need to overcome it, particularly for aggressive tumors such as pancreatic cancer, is very high. Aberrant activation of an epithelial–mesenchymal transition (EMT) and an associated cancer stem cell phenotype are considered a major cause of therapy resistance. Particularly, the EMT‐activator ZEB1 was shown to confer stemness and resistance. We applied a systematic, stepwise strategy to interfere with ZEB1 function, aiming to overcome drug resistance. This led to the identification of both its target gene miR‐203 as a major drug sensitizer and subsequently the class I HDAC inhibitor mocetinostat as epigenetic drug to interfere with ZEB1 function, restore miR‐203 expression, repress stemness properties, and induce sensitivity against chemotherapy. Thereby, mocetinostat turned out to be more effective than other HDAC inhibitors, such as SAHA, indicating the relevance of the screening strategy. Our data encourage the application of mechanism‐based combinations of selected epigenetic drugs with standard chemotherapy for the rational treatment of aggressive solid tumors, such as pancreatic cancer. Synopsis Therapy resistance is a major problem in cancer medicine. Based on the identification of novel mediators of ZEB1‐associated therapy resistance, the HDAC inhibitor mocetinostat is found to efficiently restore drug sensitivity in aggressive cancer cells. Strategy to counteract the well‐known cancer‐promoting functions of the EMT inducer ZEB1. Identification of the stemness‐inhibiting microRNA miR‐203 as major ZEB1 target inducing drug sensitivity. Identification of the class I HDAC inhibitor mocetinostat as drug to interfere with ZEB1 function and overcome ZEB1‐associated drug resistance. Mocetinostat has better effects in combination with chemotherapeutics compared to other HDACis, such as SAHA. Blueprint for further drug screens with reduction in ZEB1 function as major readout. Graphical Abstract Therapy resistance is a major problem in cancer medicine. Based on the identification of novel mediators of ZEB1‐associated therapy resistance, the HDAC inhibitor mocetinostat is found to efficiently restore drug sensitivity in aggressive cancer cells.

The senescence of bone marrow mesenchymal stem cells (BMSCs) contributes to the development of degenerative skeletal conditions. To date, the molecular mechanism resulting in BMSC senescence has not been fully understood. In this study, we identified a small non‐coding RNA, miR‐203‐3p, the expression of which was elevated in BMSCs from aged mice. On the other hand, overexpression of miR‐203‐3p in BMSCs from young mice reduced cell growth and enhanced their senescence. Mechanistically, PDZ‐linked kinase (PBK) is predicted to be the target of miR‐203‐3p. The binding of miR‐203‐3p to Pbk mRNA could decrease its expression, which in turn inhibited the ubiquitination‐mediated degradation of p53. Furthermore, the intravitreal injection of miR‐203‐3p‐inhibitor into the bone marrow cavity of aged mice attenuated BMSC senescence and osteoporosis in aged mice. Collectively, these findings suggest that targeting miR‐203‐3p to delay BMSC senescence could be a potential therapeutic strategy to alleviate age‐related osteoporosis. This study indicates that inhibiting miR‐203‐3p (partly via the PBK/p53 signaling pathway) improves cell growth dynamics and slows the process of cellular senescence, rejuvenating senescent BMSCs. Furthermore, it presents a new potential target for delaying age‐related osteoporosis.

Heart aging is a prevalent cause of cardiovascular diseases among the elderly. NAD+ depletion is a hallmark feature of aging heart, however, the molecular mechanisms that affect NAD+ depletion remain unclear. In this study, we identified microRNA‐203 (miR‐203) as a senescence‐associated microRNA that regulates NAD+ homeostasis. We found that the blood miR‐203 level negatively correlated with human age and its expression significantly decreased in the hearts of aged mice and senescent cardiomyocytes. Transgenic mice with overexpressed miR‐203 (TgN (miR‐203)) showed resistance to aging‐induced cardiac diastolic dysfunction, cardiac remodeling, and myocardial senescence. At the cellular level, overexpression of miR‐203 significantly prevented D‐gal‐induced cardiomyocyte senescence and mitochondrial damage, while miR‐203 knockdown aggravated these effects. Mechanistically, miR‐203 inhibited PARP1 expression by targeting its 3′UTR, which helped to reduce NAD+ depletion and improve mitochondrial function and cell senescence. Overall, our study first identified miR‐203 as a genetic tool for anti‐heart aging by restoring NAD+ function in cardiomyocytes. With advancing age, the expression of miR‐203 markedly decreases. MiR‐203 downregulates PARP1 expression by specifically targeting its 3′UTR, leading to a mitigation of NAD+ depletion and enhancement of mitochondrial function, ultimately mitigating cellular senescence. Our research highlights miR‐203 as a genetic tool for improving cardiac dysfunction by reinstating NAD+ levels in aging murine.

Involvement of the RGS17 oncogene in the promotion of non‐small‐cell lung cancer (NSCLC) has been reported, but the regulation mechanism in NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand the role of miRNAs in Regulator of G Protein Signaling 17 (RGS17)‐induced NSCLC, we showed that miR‐203 was downregulated during tumorigenesis, and inhibited the proliferation and invasion of lung cancer cells. We then determined whether miR‐203 regulated NSCLC by targeting RGS17. To characterize the regulatory effect of miR‐203 on RGS17, we used lung cancer cell lines, A549 and Calu‐1, and the constructed miR‐203 and RGS17 overexpression vectors. The CCK8 kit was used to determine cell proliferation, and the Transwell® assay was used to measure cell invasion and migration. RT‐PCR, western blots, and immunofluorescence were used to analyze expression of miR‐203 and RGS17, and the luciferase reporter assay was used to examine the interaction between miR‐203 and RGS17. Nude mice were used to characterize in vivo tumor growth regulation. Expression of miR‐203 inhibited proliferation, invasion, and migration of lung cancer cell lines A549 and Calu‐1 by targeting RGS17. The regulatory effect of miR‐203 was inhibited after overexpression of RGS17. The luciferase reporter assay showed that miR‐203 downregulated RGS17 by direct integration into the 3′‐UTR of RGS17 mRNA. In vivo studies showed that expression of miR‐203 significantly inhibited growth of tumors. Taken together, the results suggested that expression of miR‐203 inhibited tumor growth and metastasis by targeting RGS17. The expression of RGS17 promoted non‐small cell lung cancer (NSCLC) cell proliferation, invasion, and migration. The expression of miR‐203 was downregulated in NSCLC. The expression of miR‐203 inhibited NSCLC proliferation, invasion, and migration by targeting RGS17.

Objective We aimed to discover the molecular mechanism of hsa_circ_0076694 (circRUNX2) on osteogenic differentiation. We also explored the interaction between circRUNX2, miR‐203 and RUNX2. Methods Clinical samples obtained from femoral neck fracture patients’ bone tissues were used to collect circRUNX2, miR‐203, and RUNX2 expression data, while their expression changes were observed in human bone mesenchymal stem cells (hBMSCs) during osteogenic differentiation. QRT‐PCR and Western blot were used to analyse levels of RNAs and proteins. Biotin pull down, RIP, RNA FISH, and Dual‐Luciferase Reporter assays demonstrated the relationship between circRUNX2, miR‐203, and RUNX2. ALP and ARS staining were used to measure the degree of osteogenic differentiation under the control of circRUNX2, miR‐203. Results CircRUNX2 were down‐regulated in osteoporotic patients’ bone tissues. CircRUNX2 could inhibit miR‐203 expression by sponging miR‐203. MiR‐203 inhibited osteogenic differentiation by targeting the 3′‐UTR of RUNX2 and down‐regulate RUNX2 expression. Overexpression of circRUNX2 promoted the expression of osteogenic differentiation‐related proteins such as RUNX2, OCN, OPN, BSP, and prevented osteoporosis. Conclusion circRUNX2 could sponge miR‐203 and enhance RUNX2 expression, thus circRUNX2 prevents osteoporosis and may provide a novel therapeutic strategy for it.

Chemotherapy for patients with metastatic colorectal cancer (CRC) is the standard of care, but ultimately nearly all patients develop drug resistance. Understanding the mechanisms that lead to resistance to individual chemotherapeutic agents may help identify novel targets and drugs that will, in turn, improve therapy. Oxaliplatin is a common component combination therapeutic regimen for use in patients with metastatic CRC, but is also used as a component of adjuvant therapy for patients at risk for recurrent disease. In this study, unbiased microRNA array screening revealed that the miR-203 microRNA is up-regulated in three of three oxaliplatin-resistant CRC cell lines, and therefore we investigated the role of miR-203 in chemoresistance. Exogenous expression of miR-203 in chemo-naïve CRC cells induced oxaliplatin resistance. Knockdown of miR-203 sensitized chemoresistant CRC cells to oxaliplatin. In silico analysis identified ataxia telangiectasia mutated (ATM), a primary mediator of the DNA damage response, as a potential target of miR-203. ATM mRNA and protein levels were significantly down-regulated in CRC cells with acquired resistance to oxaliplatin. Using TCGA database, we identified a significant reverse correlation of miR-203 and ATM expression in CRC tissues. We validated ATM as a bona fide target of miR-203 in CRC cells. Mutation of the putative miR-203 binding site in the 3′ untranslated region (3′UTR) of the ATM mRNA abolished the inhibitory effect of miR-203 on ATM. Furthermore, stable knockdown of ATM induced resistance to oxaliplatin in chemo-naïve CRC cells. This is the first report of oxaliplatin resistance in CRC cells induced by miR-203-mediated suppression of ATM. •miR-203 was up-regulated in oxaliplatin-resistant colorectal cancer (CRC) cells.•Knockdown of miR-203 sensitized chemoresistant CRC cells to oxaliplatin.•ATM levels were significantly down-regulated in oxaliplatin-resistant CRC cells.•Stable knockdown of ATM induced resistance to oxaliplatin in chemo-naïve CRC cells.•Oxaliplatin resistance in CRC cells induced by miR-203-mediated suppression of ATM.

Objective We aimed to investigate the roles of the lncRNA MALAT1 in renal cell carcinoma (RCC) progression. Methods qRT‐PCR was used for the assessment of BIRC5, miRNA‐203 and MALAT1 expression. Furthermore, the targeted relationships between miR‐203 and BIRC5, as well as MALAT1 and miR‐203, were predicted by the miRanda/starBase database and verified by dual‐luciferase reporter gene assay. The effects of MALAT1, miRNA‐203 and BIRC5 on cell proliferation, cell cycle, cell apoptosis, cell invasion and cell migration were studied by using CCK‐8, flow cytometry, transwell and wound healing assays, respectively. In addition, the effects of MALAT1 on RCC tumorigenesis were evaluated in vivo by nude mouse tumorigenesis. Results The expression levels of BIRC5 and MALAT1 were higher in RCC tissues and cell lines than in adjacent normal tissues and a normal renal cortex proximal tubule epithelial cell line. In contrast, the expression of miRNA‐203 in RCC tissues and cell lines was higher than that in adjacent normal tissues and a normal renal cortex proximal tubule epithelial cell line. BIRC5 and MALAT1 promoted cell proliferation yet decreased the percentage of RCC cells at G0/G1 phase. Conclusions Our study demonstrated that MALAT1 functions as a miR‐203 decoy to increase BIRC5 expression in RCC.

High fructose intake is a risk factor for liver fibrosis. Polydatin is a main constituent of the rhizome of Polygonum cuspidatum, which has been used in traditional Chinese medicine to treat liver fibrosis. However, the underlying mechanisms of fructose‐driven liver fibrosis as well as the actions of polydatin are not fully understood. In this study, fructose was found to promote zinc finger E‐box binding homeobox 1 (ZEB1) nuclear translocation, decrease microRNA‐203 (miR‐203) expression, increase survivin, activate transforming growth factor β1 (TGF‐β1)/Smad signalling, down‐regulate E‐cadherin, and up‐regulate fibroblast specific protein 1 (FSP1), vimentin, N‐cadherin and collagen I (COL1A1) in rat livers and BRL‐3A cells, in parallel with fructose‐induced liver fibrosis. Furthermore, ZEB1 nuclear translocation‐mediated miR‐203 low‐expression was found to target survivin to activate TGF‐β1/Smad signalling, causing the EMT in fructose‐exposed BRL‐3A cells. Polydatin antagonized ZEB1 nuclear translocation to up‐regulate miR‐203, subsequently blocked survivin‐activated TGF‐β1/Smad signalling, which were consistent with its protection against fructose‐induced EMT and liver fibrosis. These results suggest that ZEB1 nuclear translocation may play an essential role in fructose‐induced EMT in liver fibrosis by targeting survivin to activate TGF‐β1/Smad signalling. The suppression of ZEB1 nuclear translocation by polydatin may be a novel strategy for attenuating the EMT in liver fibrosis associated with high fructose diet.

The circRNA circAGFG1 is reported to be important in triple‐negative breast cancer progression. However, the mechanism of circAGFG1 in non‐small‐cell lung cancer (NSCLC) remains unknown. In this study, expression of circAGFG1 was determined by real‐time PCR in 20 pairs of NSCLC tissues and adjacent tissues. Next, functional experiments with circAGFG1 were performed in vitro to evaluate the role of circAGFG1 in tumor metastasis and growth. Meanwhile, a dual luciferase reporter assay, RNA pull‐down and RNA immunoprecipitation experiments were used to explore the interaction between circAGFG1 and miR‐203. Our results revealed that expression levels of circAGFG1 and miR‐203 are upregulated in non‐small‐cell lung cancer tissues. CircAGFG1 enhances NSCLC cell proliferation, invasion, migration and epithelial‐mesenchymal transition in vitro. Mechanistic analyses indicated that circAGFG1 acts as a sponge for miR‐203 to repress the effect of miR‐203 on its target, ZNF281. In conclusion, our study suggests that circAGFG1 promotes NSCLC growth and metastasis though a circAGFG1/miR‐203/ZNF281 axis and may represent a novel therapeutic target.

Background Sarcopenia frequently occurs in metastatic cancer patients. Emerging evidence has revealed that various secretory products from metastatic tumours can influence host organs and promote sarcopenia in patients with malignancies. Furthermore, the biological functions of microRNAs in cell‐to‐cell communication by incorporating into neighbouring or distal cells, which have been gradually elucidated in various diseases, including sarcopenia, have been elucidated. Methods We evaluated psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) using pre‐operative computed tomography imaging in 183 colorectal cancer (CRC) patients. miR‐203 expression levels in CRC tissues and pre‐operative serum were evaluated using quantitative polymerase chain reaction. Functional analysis of miR‐203 overexpression was investigated in human skeletal muscle cells (SkMCs), and cells were analysed for proliferation and apoptosis. Expressions of several putative miR‐203 target genes (CASP3, CASP10, BIRC5, BMI1, BIRC2, and BIRC3) in SKMCs were validated. Results A total of 183 patients (108 men and 75 women) were included. The median age of enrolled patients at diagnosis was 68.0 years (range 35–89 years). High IMAC status significantly correlated with female gender (P = 0.004) and older age (P = 0.0003); however, no other clinicopathological factors correlated with IMAC status in CRC patients. In contrast, decreased PMI significantly correlated with female gender (P = 0.006) and all well‐established disease development factors, including advanced T stage (P = 0.035), presence of venous invasion (P = 0.034), lymphovascular invasion (P = 0.012), lymph node (P = 0.001), distant metastasis (P = 0.002), and advanced Union for International Cancer Control tumour–node–metastasis stage classification (P = 0.0004). Although both high IMAC status and low PMI status significantly correlated with poor overall survival (IMAC: P = 0.0002; PMI: P < 0.0001; log‐rank test) and disease‐free survival (IMAC: P = 0.0003; PMI: P = 0.0002; log‐rank test), multivariate Cox's regression analysis revealed that low PMI was an independent prognostic factor for both overall survival (hazard ratio: 4.69, 95% confidence interval (CI): 2.19–10, P = 0.0001) and disease‐free survival (hazard ratio: 2.33, 95% CI: 1.14–4.77, P = 0.021) in CRC patients. Serum miR‐203 expression negatively correlated with pre‐operative PMI level (P = 0.0001, ρ = −0.25), and multivariate logistic regression analysis revealed that elevated serum miR‐203 was an independent risk factor for myopenia (low PMI) in CRC patients (odds ratio: 5.16, 95% CI: 1.8–14.8, P = 0.002). Overexpression of miR‐203 inhibited cell proliferation and induced apoptosis via down‐regulation of BIRC5 (survivin) expression in human SkMC line. Conclusions Assessment of serum miR‐203 expression could be used for risk assessment of myopenia, and miR‐203 might be a novel therapeutic target for inhibition of myopenia in CRC.