Saifei He

MicroRNA‑497 inhibits cellular proliferation, migration and invasion of papillary thyroid cancer by directly targeting AKT3

Thyroid cancer is the most common tumor of the endocrine organs. Emerging studies have indicated the critical roles of microRNAs (miRs) in papillary thyroid cancer (PTC) formation and progression through function as tumor suppressors or oncogenes. The present study investigated the expression level and biological roles of miR-497 in PTC and its underlying mechanisms. It was demonstrated that the expression level of miR-497 was reduced in both PTC tissues and cell lines. Enforced expression of miR-497 suppressed PTC cell proliferation, migration and invasion. According to bioinformatics analysis, a luciferase reporter assay, reverse transcription-quantitative polymerase chain reaction and western blotting, RAC-γ serine/threonine-protein kinase (AKT3) was demonstrated to be the direct target gene of miR-497. In addition, AKT3 expression increased in PTC tissues and negatively correlated with miR-497 expression. Furthermore, downregulation of AKT3 also suppressed cell proliferation, migration and invasion of PTC, which had similar roles to miR-497 overexpression in PTC cells. Taken together, these results suggested that this newly identified miR-497/AKT3 signaling pathway may contribute to PTC occurrence and progression. These findings provide novel potential therapeutic targets for the therapy of PTC.

microRNA‑605 promotes cell proliferation, migration and invasion in non‑small cell lung cancer by directly targeting LATS2

Lung cancer is the most common cause of cancer- associated mortality for men and women worldwide. An increasing number of studies have reported that the abnormal expression of microRNAs contributes to the pathogenesis of the majority of human cancer types, including non-small cell lung cancer (NSCLC). The present study aimed to measure microRNA-650 (miR-650) expression in NSCLC and evaluate its function in NSCLC cells. Reverse transcription-quantitative polymerase chain reaction was used to determine miR-650 expression in NSCLC tissue samples and cell lines. Assays for cell proliferation, migration and invasion were performed to investigate the roles of miR-650 on NSCLC progression. Furthermore, the mechanisms underlying the effects of miR-650 on NSCLC cell growth and metastasis were determined. In the current study, miR-650 was demonstrated to be highly expressed in NSCLC tissue samples and cell lines. Inhibition of expression of miR-650 suppressed NSCLC cell proliferation, migration and invasion in vitro. Additionally, large tumor suppressor kinase 2 (LATS2) was identified as a direct target gene of miR-650 in NSCLC. LATS2 was revealed to be significantly downregulated in NSCLC tissues and was negatively correlated with miR-650 expression. Notably, LATS2 re-expression decreased NSCLC cell proliferation, migration and invasion; similar to the effects induced by miR-650 underexpression. In conclusion, the results of the current study suggest that miR-650 may serve as an oncogene by direct targeting LATS2 in NSCLC formation and progression.

The Oncogenic Role of Tribbles 1 in Hepatocellular Carcinoma Is Mediated by a Feedback Loop Involving microRNA-23a and p53

Hepatocellular carcinoma (HCC) is a common malignancy associated with a high risk of recurrence and metastasis and a poor prognosis. Here, we examined the involvement of the pseudokinase Tribbles 1 (TRIB1), a scaffold protein associated with several malignancies, in HCC and investigated the underlying mechanisms. TRIB1 was upregulated in HCC tissues and cell lines in correlation with low levels of p53. TRIB1 gain and loss of function experiments indicated that TRIB1 promoted HCC cell viability concomitant with the downregulation of p53, and induced HCC cell migration, invasion, and epithelial-mesenchymal transition. TRIB1 was identified as a target of microRNA-23a (miR-23a), and miR-23a overexpression downregulated TRIB1 and upregulated p53 in HCC cells. Ectopic expression of TRIB1 upregulated β-catenin and its effectors c-myc and MMP-7 in a p53-dependent manner. TRIB1 silencing inhibited tumor growth and promoted apoptosis in vivo via a mechanism that would involve the modulation of p53 and β-catenin signaling. The present results indicate that TRIB1 promotes HCC tumorigenesis and invasiveness via a feedback loop that involves the modulation of its expression by miR-23a with the likely downregulation of p53, and suggest the involvement of the β-catenin signaling pathway. These findings suggest potential targets for the treatment of HCC and therefore merit further investigation.

MicroRNA-511 inhibits cellular proliferation and invasion in colorectal cancer by directly targeting hepatoma-derived growth factor

Dysregulated microRNAs (miRNAs) expression is involved in the occurrence and development of colorectal cancer (CRC) through the regulation of various important physiological events. Hence, miRNAs may be used as effective targets for CRC treatment; however, this hypothesis warrants further investigation. MiRNA-511 (miR511) plays vital roles in the progression of different tumour types. However, the expression, exact role and the mechanisms underlying the regulation of colorectal carcinogenesis and progression by miR-511 remain poorly understood. This study presents that miR-511 expression was decreased in CRC tissues and cell lines as compared with that in adjacent non-neoplastic tissues and normal human colon epithelium cell lines, respectively. The enforced expression of miR-511 in CRC cells significantly reduced cell proliferation and invasion. Hepatoma-derived growth factor (HDGF) was mechanically validated as a direct target of miR-511 in CRC. Furthermore, miR-511 was negatively associated with HDGF in CRC tissues. The restored HDGF expression can abrogate the tumour suppressive roles of miR-511 in CRC cells. More importantly, miR-511 overexpression suppressed the PI3K/AKT signalling pathway in CRC. These results suggest that miR-511 can potentially serve as a therapeutic target for the therapy of patients with CRC.

ARHGAP24 regulates cell ability and apoptosis ofcolorectal cancer cells via the regulation of P53

Colorectal cancer is a human malignancy ranked the third highest of the global incidence of malignant tumors. Rho GTPase-activating proteins (RHOGAPs) were identified functional in several processes of tumors. In the present study, through reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis, expression of Rho GTPase-activating protein 24 (ARHGAP24) and p53 was measured in colorectal cancer tissues, which was lower than that in adjacent normal tissues, revealing that ARHGAP24 may be implicated in the progress of colorectal cancer and in vitro, overexpression of ARHGAP24 in LoVo and HCT116 cells inhibited the cell ability and enhanced cell apoptosis, and accompanied with high protein expression of p53, p21 and Bax. Further, addition of p53 inhibitor PFT-α had an antagonistic effect on cell proliferation and apoptosis of LoVo and HCT116 cells induced by ARHGAP24 overexpression. In addition, the expression of p21 and Bax was positively correlated with p53 expression. All of the above data demonstrated that ARHGAP24 was likely to be a tumor suppressor in colorectal cancer and may function closely related to p53, p21 and Bax. We inferred that ARHGAP24 may be a novel target for in-depth study of colorectal cancer.

Combined effects of Lenvatinib and iodine‑131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress

Nasopharyngeal carcinoma (NPC) is a type of malignant tumor characterized by high invasiveness, metastatic potential and worldwide incidence among patients with head and neck cancer. It has previously been demonstrated that Lenvatinib (LEB) is an efficient anti-cancer agent by multi-targeting of tyrosine kinase inhibitors. Iodine-131 (I-131) therapy has been accepted for the treatment of thyroid cancer and other carcinomas. In the present study, the combined effects of LEB and I-131 were investigated on NPC and the potential signal pathway mediated by LEB and I-131 on NPC cells was explored. Inhibitory effects of LEB and I-131 for NPC cells growth were investigated via MTT assay. Migration and invasion of NPC cells was studied by aggression assays following incubation of LEB and I-131. Apoptosis of NPC cells and tissues were analyzed via flow cytometry and TUNEL assay, respectively. Apoptosis-related gene expression levels in NPC cells following treatment with LEB and I-131 were determined by western blotting. Endoplasmic reticulum (ER) stress in NPC cells were analyzed in NPC cells and tumor tissues. Immunohistochemistry was used to analyze the efficacy of LEB and I-131 in NPC-tumor bearing mice. The results demonstrated that combined treatment of LEB and I-131 significantly inhibited growth, apoptosis, migration and invasion of NPC cells compared with single agent therapy. Apoptosis-related gene expression levels of caspase-3 and caspase-9 were upregulated by LEB and I-131, whereas B call lymphoma-2, and P53 were downregulated in NPC cells and tumor tissues. In addition, signal mechanism analysis demonstrated that combined treatment of LEB and I-131 promoted expression levels of activating transcription factor 6, inositol-requiring protein 1 (IER1), protein kinase RNA-like endoplasmic reticulum kinase (RERK), and C/EBP homologous protein in NPC cells. Furthermore, combined treatment of LEB and I-131 markedly inhibited in vivo growth of NPC and further prolonged survival of experimental mice compared with single agent and control groups. Immunohistochemistry indicated that c-jun N-terminal kinase and Caspase-3 were increased in NPS tumor tissues in xenograft models treated with LEB and I-131. Apoptotic bodies were also increased in tumors treated by LEB and I-131. In conclusion, these findings indicate that combined treatment of LEB and I-131 may inhibit NPC growth and aggression through upregulation of ER stress, suggesting combined treatment of LEB and I-131 may be a potential therapeutic schedule for the treatment of NPC.

GINS2 promotes cell proliferation and inhibits cell apoptosis in thyroid cancer by regulating CITED2 and LOXL2

To explore the mechanisms of GINS2 on cell proliferation and apoptosis in thyroid cancer (TC) cells. Expressions of GINS2 were inhibited in K1 and SW579 cells using gene interference technology. The abilities of proliferation and apoptosis, and cell cycle were determined by MTT assay and flow cytometric assay. The downstream molecules of GINS2 were searched by microarray and bioinformatics and validated by qRT-PCR and western blotting. In the in vivo study, the tumor growth was compared and the whole-body fluorescent imaging was analyzed. After GINS2 was interfered, cell proliferation was significantly inhibited (P < 0.01) and apoptosis rate increased (P < 0.01) in both K1 and SW579 cells. Cell cycle changed significantly in K1 cells, but not in SW579 cells. With bioinformatics upstream analysis, TGF-β1 was found as the most significantly upstream regulator. Expressions of TGF-β1 and its downstream target molecules CITED2 and LOXL2 were validated and found downregulated significantly in mRNA and protein levels (P < 0.05). The results of the nude mouse xenograft assay suggested that the volume and weight of tumor in ones infected with shGINS2 were statistically smaller than controls (P < 0.05). GINS2 plays an important role in cell proliferation and apoptosis of thyroid cancer by regulating the expressions of CITED2 and LOXL2, which may be a potential biomarker for diagnosis or prognosis and a drug target for therapy.

MicroRNA‑139 targets fibronectin 1 to inhibit papillary thyroid carcinoma progression

Thyroid cancer is the most common tumour of the endocrine system, and its incidence rate has markedly increased over the past several decades. Aberrantly expressed microRNAs (miRNAs) are reportedly involved in the formation and progression of papillary thyroid carcinoma (PTC) by regulating their target genes. Thus, miRNAs may be potential molecular biomarkers for the prediction and prognosis of PTC, and also as novel therapeutic targets for patients with PTC. miR-139 has recently been reported to be aberrantly expressed in several types of cancer. However, the expression levels, biological functions and the associated molecular mechanism of miR-139 in PTC have not been clearly elucidated. The results of the present study revealed that miR-139 expression was downregulated in PTC tissues and cell lines when compared with adjacent normal tissues and normal human thyroid cells, respectively. The restoration of miR-139 expression suppressed cellular proliferation and invasion in PTC in vitro. In addition, fibronectin 1 (FN1) was identified as a direct target of miR-139 in PTC. Furthermore, FN1 was highly expressed in PTC tissues and negatively associated with miR-139 expression. Moreover, the tumour-suppressive effects of miR-139 overexpression on PTC cells were ameliorated by ectopic FN1 expression. To the best of our knowledge, the present study is the first to demonstrate that miR-139 may serve as a tumour suppressor and serve important roles in inhibiting tumourigenesis by targeting FN1 in PTC cells.

MicroRNA‑495 suppresses cell proliferation and invasion of hepatocellular carcinoma by directly targeting insulin‑like growth factor receptor‑1

Hepatocellular carcinoma (HCC) is the fifth most common malignancy and second-most frequent cause of cancer-associated deaths worldwide. Previously, increasing studies report that microRNAs (miRNAs/miRs) are abnormally expressed in various types of human cancers and may participate in the tumourigenesis and tumour development of HCC. miRNA-based targeted therapy is effective against different molecular targets and may increase the sensitisation of cancer cells to therapy by several folds. Therefore, further validation of potentially important miRNAs involved in HCC initiation and progression may provide valuable insights into the treatment of patients with HCC. miR-495 is abnormally expressed in multiple types of human cancers. However, the expression level and roles of miR-495 in HCC have yet to be completely elucidated. In the present study, miR-495 expression was frequently downregulated in HCC tissues and cell lines, and miR-495 expression levels were significantly correlated with tumour size, tumor-node-metastasis (TNM) stage and lymph node metastasis in patients with HCC. Functional assays revealed that miR-495 overexpression inhibited cell proliferation and invasion in HCC. Insulin-like growth factor receptor-1 (IGF1R) was identified as a direct target gene of miR-495 in HCC. IGF1R was upregulated in HCC tissues and negatively correlated with miR-495 expression level. The upregulation of IGF1R rescued the miR-495-induced tumour-suppressive roles in HCC cell proliferation and invasion, and the restored miR-495 expression inactivated the protein kinase B and extracellular regulated protein kinase signalling pathways in HCC. These results provide novel insights into the molecular mechanism underlying HCC progression, and suggest that miR-495 may be investigated as a novel therapeutic target for patients with this disease.