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An increasing body of evidence indicates the involvement of microRNAs (miRNAs/miRs) in the initiation and progression of colorectal cancer (CRC). miR-296-5p was recently identified as a tumor suppressor in a variety of human cancer types; however, its function in CRC remains largely unknown. The present study demonstrated that the expression of miR-296-5p was significantly downregulated in CRC tissues and cell lines. The overexpression of miR-296-5p markedly inhibited proliferation, and induced cell cycle arrest and apoptosis in CRC cells. Bioinformatics analysis suggested that high mobility group AT-hook 1 (HMGA1) may be a target of miR-296-5p in CRC cells. Further experiments showed that miR-296-5p bound the 3'-untranslated region of HMGA1 and decreased its expression in CRC cells. HMGA1 was overexpressed in CRC tissues and was inversely correlated with the expression of miR-296-5p. The restoration of HMGA1 significantly reversed the inhibitory effect of miR-296-5p on the proliferation of CRC cells. Overall, the findings of the present study indicate that miR-296-5p suppressed the progression of CRC, at least partially via targeting HMGA1. Thus, miR-296-5p is a potential target for novel therapies in CRC.

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[This corrects the article DOI: 10.3389/fonc.2020.00589.].

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MicroRNAs (miRNAs) have been implicated in regulating the development and metastasis of human cancers. MiR-221 is reported to be an oncogene in multiple cancers, including bladder cancer (BC). Deregulation of autophagy is associated with multiple human malignant cancers. Whether and how miR-221 regulates autophagy and how miR-221 has been regulated in BC are poorly understood. This study explored the potential functions and mechanisms of miR-221 in the autophagy and tumorigenesis of BC. We showed that the downregulation of miR-221 induces autophagy via increasing TP53INP1 (tumor protein p53 inducible nuclear protein 1) and inhibits migration and invasion of BC cells through suppressing activation of extracellular signal-regulated kinase (ERK). Furthermore, the expression of miR-221 is regulated by high-mobility group AT-hook 1 (HMGA1) which is overexpressed in BC. And both miR-221 and HMGA1 are correlated with poor patient survival in BC. Finally, the downregulation of HMGA1 suppressed the proliferative, migrative, and invasive property of BC by inducing toxic autophagy via miR-221/TP53INP1/p-ERK axis. Collectively, our findings demonstrate that the downregulation of miR-221 and HMGA1 mediates autophagy in BC, and both of them are valuable therapeutic targets for BC.

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Extensive research has shown that LINC00963 is aberrantly expressed in human cancers, and that dysregulation of LINC00963 is implicated in the initiation and progression of human cancers. The expression and functions of LINC00963 in breast cancer are still unclear. Our aims were to measure the expression of LINC00963 in breast cancer, determine its effects on malignant behaviors of tumor cells, and uncover the molecular events underlying the actions of LINC00963 in breast cancer. Herein, LINC00963 was found to be overexpressed in breast cancer samples, and its overexpression was correlated with lymph node metastasis, TNM stage and differentiation grade. Patients with breast cancer harboring higher LINC00963 expression showed shorter overall survival than did the patients with lower LINC00963 expression. Functional experiments revealed that depletion of LINC00963 inhibited breast cancer cell proliferation, migration, and invasion and facilitated apoptosis in vitro and impaired tumor growth in vivo. Mechanism investigation revealed that LINC00963 can interact with microRNA-625 (miR-625). LINC00963 worked as a competitive endogenous RNA for miR-625 to weaken the suppressive effect of miR-625 on high mobility group AT-hook 1 (HMGA1) in breast cancer cells. Furthermore, miR-625 inhibition and HMGA1 restoration both abrogated the effects of LINC00963 silencing on breast cancer cells. Our findings indicate that the LINC00963-miR-625-HMGA1 pathway plays an important role in the malignancy of breast cancer in vitro and in vivo. Hence, targeting this pathway may be a novel strategy against breast cancer.

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Long noncoding RNAs (lncRNAs) have been confirmed to be aberrantly expressed in various diseases including tumors. Recently, a new tumor-related lncRNA, lncRNA TRPM2 antisense RNA (TRPM2-AS), was shown to be involved in many tumors, such as lung cancer and breast cancer. However, the expression and role of TRPM2-AS in the development of gastric cancer (GC) have not been elucidated. In the current study, we provided evidence that the expression levels of TRPM2-AS were increased in both GC tissues and cell lines. We also showed that overexpression of TRPM2-AS was modulated by ELK1, a transcription factor. The results of clinical assays showed that higher expressions of TRPM2-AS were significantly related with invasion depth, TNM stage, lymphatic metastasis, and shorter overall survival. Further clinical assays using multivariate analysis suggested that TRPM2-AS expression was an independent prognostic factor in patients with GC. Functional experiments illustrated that depression of TRPM2-AS suppressed proliferation, migration, and invasion in GC cells. In terms of mechanism, we found that TRPM2-AS directly inhibited miR-195, which targeted the 3'-untranslated region of high-mobility group AT-hook 1 (HMGA1) messenger RNA. Overall, these findings revealed that ELK1-induced overexpression of TRPM2-AS promoted the development and progression of GC in part through miR-195/HMGA1 signaling axis, and established its candidacy as a new cancer biomarker for GC patients.

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microRNAs (miRNAs) are frequently aberrantly expressed in osteosarcoma (OS) and are implicated in its development. Dysregulation of miR-758 has been reported in various human malignancies. However, whether miR-758 is involved in the oncogenesis and progression of OS remains unclear. In this study, reverse transcription-quantitative polymerase chain reaction was performed to detect miR-758 expression in OS tissues and cell lines. A series of functional experiments were employed to explore the regulatory effects of miR-758 on the malignant behaviors of OS cells both in vitro and in vivo. The molecular mechanisms underlying the activity of miR-758 in OS cells were also investigated. miR-758 was significantly downregulated in OS tissues and cell lines, and a low miR-758 level was correlated with tumor size, clinical stage, and distant metastasis of patients with OS. OS patients with low miR-758 level exhibited poorer overall survival and worse disease-free survival rates compared to patients with high miR-758 level. In addition, functional assays revealed that miR-758 overexpression led to a significant decrease in OS cell growth and metastasis in vitro, whereas miR-758 inhibition had the opposite effect on OS cells. miR-758 reduced the tumorous growth of OS cells in vivo. Furthermore, high mobility group AT-hook 1 (HMGA1) was identified as a direct target of miR-758 in OS cells. HMGA1 was highly expressed in OS tissues, and its expression was inversely correlated with miR-758 expression. HMGA1 silencing exerted an effect similar to that induced by miR-758 upregulation in OS cells. Restored HMGA1 expression abolished the effects of miR-758 on the malignant phenotypes of OS cells. Moreover, miR-758 regulated the Wnt/ß-catenin pathway in OS cells in vitro and in vivo. To the best of our knowledge, this is the first study to demonstrate that miR-758 may inhibit the aggressive behavior of OS cells in vitro and in vivo by directly targeting HMGA1 and regulating the Wnt/ß-catenin pathway. These results will aid in elucidating the roles of miR-758 and suggest that the miR-758/HMGA1/Wnt/ß-catenin pathway represents a potential therapeutic target in OS.

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BACKGROUND: Obesity is characterized by the excess accumulation of adipose tissues, mainly composed of adipocytes. The differentiation of adipocytes is one of the major events in the process of adipogenesis. Among various adipogenic transcription factors, CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferators-activated receptor γ (PPARγ) have been identified as essential regulators of adipocyte differentiation. METHODS: RT-qPCR assay was conducted to detect the expression of microRNA-142a-3p (miR-142a-3p), high-mobility group AT-hook 1 (HMGA1) mRNA, C/EBPα mRNA, and PPARγ mRNA. Western blot assay was performed to measure the protein levels of HMGA1, C/EBPα and PPARγ. Bioinformatics analysis and luciferase reporter assay were carried out to explore the interaction between miR-142a-3p and HMGA1. RESULTS: miR-142a-3p expression was notably increased and HMGA1 expression was markedly reduced during 3T3-L1 preadipocyte differentiation. Functional analysis revealed that miR-142a-3p overexpression promoted 3T3-L1 preadipocyte differentiation. Further investigations on molecular mechanisms showed that HMGA1 was a target of miR-142a-3p in 3T3-L1 preadipocytes. Moreover, the knockdown of HMGA1 induced 3T3-L1 preadipocyte differentiation. Additionally, HMGA1 silencing abolished miR-142a-3p deficiency-mediated inhibitory effect on 3T3-L1 preadipocyte differentiation. CONCLUSION: MiR-142a-3p overexpression facilitated 3T3-L1 preadipocyte differentiation by targeting HMGA1, highlighting the importance of miR-142a-3p, HMGA1 and the miR-142a-3p/HMGA1 axis in adipogenesis.

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High Mobility Group AT-hook 1 (HMGA1) was identified as a target of miR-214 in human cervical and colorectal cancers (CaCx and CRC) in a previous study. While the expression of miR-214 remains suppressed, HMGA1 behaves as a potent oncogene and plays crucial roles in several aberrant signalling pathways by interacting with intermediates like RELA, CTNNB1, STAT3, and TP53 in CaCx and CRC. Hypothetically, miR-214 should be able to regulate the stabilization of some of these intermediates through the regulation of HMGA1. This was assessed by ectopically expressing miR-214 or complementarily, by inhibiting the expression of HMGA1. In promoter luciferase assays, miR-214 inhibited NF-κB and Wnt activities but elevated TP53 activity in cancer cells. Further, miR-214 suppressed the expression of HMGA1, RELA, CTNNB1, and STAT3 while elevating TP53 levels, similar to when small interfering RNA (siRNA) against HMGA1 was used, as revealed by Western blotting. It is suggested that poor expression of miR-214, commonly reported in CaCx and CRC tissues, may not only result in the sustained expression of HMGA1 but also that of RELA, CTNNB1, and STAT3, and a congruent suppression of TP53 during cancer initiation/progression. These several states are, however, reversed when miR-214 is reintroduced and could explain the tumour suppressive functions observed in earlier studies. Further studies are, however, required to reveal how microRNA-mediated regulation of HMGA1 expression may affect individual signalling pathways in CaCx and CRC. Current results reveal that miR-214 is not only able to regulate the expression of its direct target, HMGA1, but also that of a few signalling intermediates like TP53, RELA, CTNNB1, and STAT3, with which HMGA1 interacts. These intermediates play crucial roles in signalling pathways commonly deregulated in human CaCx and CRC. Hence, it is proposed that miR-214 might act as a tumour suppressor by regulating several aberrant signalling pathways through HMGA1. This knowledge has the potential to help design novel therapeutic strategies in CaCx and CRC.

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Objective To investigate the effects of siRNA mediated HMGA 1 silence on proliferation and the gene expression of HMGA1 ,α-SMA and E-cadherin in activated hepatic stellate cells and its mechanisms .Methods Synthetic HMGA1 siRNA was transfected into LX-2 cells to silence the HMGA1 gene .The expression level of HMGA1 ,α-SMA and E-cadherin was determined by RT-PCR and Western blot experiments .LX-2 cell proliferation was assessed by M TT assay .Results The best inhibited effect was HMGA1-siRNA-1 .Compared with control group ,the cell proliferation and the mRNA and protein expression of HMGA 1 ,α-SMA in TGF-β1 group and TGF-β1 + NC-siRNA group were significantly increased (P 0 .05) ,while the expression of E-cadherin in TGF-β1 group and TGF-β1 + NC-siRNA group were significantly decreased compared with control group (P< 0 .05) .Meanwhile ,the cells in TGF-β1 + HMGA1 siRNA group showed significantly decreased proliferation level ,down-regulated mRNA and protein expression of HMGA 1 ,α-SMA but up-regulated expression of E-cadherin compared with TGF-β1 group and TGF-β1 + NC-siRNA group(P< 0 .05) .Conclusion HMGA1 interference could signifi-cantly down-regulate the expression of HMGA1 in LX-2 cells cultured with TGF-β1 ,thus inhibiting the proliferation and activation of the cells .

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BACKGROUND: MicroRNA-26a (miR-26a) functions as a tumor suppressor by regulating its direct target gene high mobility group AT-hook 1 (HMGA1). This study was aimed to investigate the associations of differential expression of miR-26a and HMGA1 with tumor progression and prognosis in urothelial bladder cancer (UBC) patients. MATERIALS AND METHODS: One hundred and twenty-six UBC patients were selected and quantitative real-time PCR was performed to detect the expression of miR-26a and HMGA1 mRNA in the respective tumors. RESULTS: Our data showed the decreased expression of miR-26a and the increased expression of HMGA1 mRNA in UBC tissues compared with corresponding non-cancerous tissues (both P<0.001). Then, the expression levels of miR-26a in UBC tissues were negatively correlated with those of HMGA1 mRNA significantly (r=-0.72, P<0.001). In addition, UBC patients with combined miR-26a downregulation and HMGA1 upregulation (miR-26a-low/HMGA1-high) more frequently had advanced pathological stage (P<0.001) and high tumor grade (P<0.001). Moreover, miR-26a-low/HMGA1-high expression was associated with a significantly shortest disease-free survival (P<0.001) and overall survival (P<0.001) of all miR-26a/HMGA1 combined expression groups. Furthermore, multivariate analysis indicated that miR-26a/HMGA1 expression was an independent prognostic factor for both disease-free survival and overall survival (both P=0.001) in UBC patients. CONCLUSION: Interaction between miR-26a and its target gene HMGA1 may contribute to the malignant progression of human UBC. Tumors with miR-26a downregulation in combination with high expression of HMGA1 showed a worse prognosis than the other tumors. Combined detection of their expression might be particularly helpful for surveillance of disease progression and treatment stratification.

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It is increasingly clear that microRNAs play a crucial role in tumorigenesis. Recently, emerging evidence suggested that miR-26a is aberrantly expressed in tumor tissues. In our study, frequent down-regulation of miR-26a was observed in 10 human bladder cancer tissues. Forced expression of miR-26a in the bladder cancer cell line T24 inhibited cell proliferation and impaired cell motility. High mobility group AT-hook 1 (HMGA1), a gene that modulates cell cycle transition and cell motility, was verified as a novel target of miR-26a in bladder cancer. These findings indicate an important role for miR-26a in the molecular etiology of bladder cancer and implicate the potential application of miR-26a in bladder cancer therapy.

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