Background Liver cancer is the second leading causes of cancer-related death globally. Pyrroline-5-carboxylate reductase 1 (PYCR1) plays a critical role in metabolic profiles of tumors. Therefore, it is necessary to explore the mechanisms of PYCR1 on cell growth and survival in hepatocellular carcinoma (HCC). Methods Protein and mRNA expression levels of PYCR1 in 140 pairs of tumor and adjacent normal liver tissues of HCC patients were analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). Expressions of PYCR1 were inhibited in BEL-7404 cells and SMMC-7721 cells using gene interference technology. The cell proliferation was detected by Celigo and MTT assay. The colony formation assay was also performed. The cell apoptosis was measured by flow cytometric assay. The effect of PYCR1 interference on tumor growth was observed by xenograft nude mice assay in vivo. The downstream pathway of PYCR1 interference was searched by microarray and bioinformatics analysis, and validated by qRT-PCR and western blot. Results PYCR1 levels were significantly up-regulated in HCC tumor tissues than adjacent normal liver tissues in both protein and mRNA levels (P < 0.01). In vitro, the cell proliferation was significantly slower in shPYCR1 group than shCtrl group in BEL-7404 and SMMC-7721 cells (P < 0.001). The colony number was significantly smaller after PYCR1 interference (P < 0.01). The percentage of apoptosis cells significantly increased in shPYCR1 group (P < 0.01). In vivo, PYCR1 interference could obviously suppress tumor growth in xenograft nude mice. The volume and weight of tumors were significantly smaller via PYCR1 interference. The c-Jun N-terminal kinase (JNK) signaling pathway significantly altered, and insulin receptor substrate 1 (IRS1) were significantly down-regulated by PYCR1 interference in both mRNA and protein levels (P < 0.001). Conclusion PYCR1 interference could inhibit cell proliferation and promote cell apoptosis in HCC through regluting JNK/IRS1 pathway. Our study will provide a drug target for HCC therapy and a potential biomarker for its diagnosis or prognosis.

Background：Hepatocellular carcinoma is one of the top five causes of cancer death. The interaction of RNA binding proteins and long no coding RNA play vital role in malignant tumor progression, and even contribute to chemoresistance.Method：RBMX and Lnc BLACAT1 were measured in HCC patient’s tissue and commercial cell lines (Huh7 and Hep3B). And there relationship was verified by Co-IP assay and Overexpression experiment. Furthermore, the cell proliferation, colony formation and drug resistant assay were performed for effect evaluation of RBMX and BLACAT1in HCC cell lines.Result：Both overexpression and positive correlation between RBMX and BLACAT1 were validated in HCC cell lines. Co-IP analysis also shows BLACAT1 could be specially bond by RBMX and increased the expression of BLACAT1. This mechanism of action is beneficial for cancer cells proliferation, anti-apoptotic, and colony formation with sorafenib treatment. Further, the autophagy level and cancer cell stemness were also improved when RBMX/BLACAT1 upregulated.Conclusion：Our study indicated that hepatoma cells can improve their proliferation, colony ability and autophagy by RBMX stabilizing BLACAT1 expression then promote HCC development and drug resistance, hence, RBMX could be considered as novel therapeutic target for HCC treatment strategies.

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.

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.

Abstract. 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.

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.

Background and Objective: GINS complex subunit 2 (GINS2), a member of the GINS complex, is involved in DNA replication. GINS2 is upregulated in a variety of aggressive tumors, such as leukemia, breast cancer, and cervical cancer. However, the role of GINS2 in pancreatic cancer has still remained elusive. In this study, PANC-1 and BxPC-3 cell lines were chosen to perform experiments in vitro. Additionally, the effects of GINS2 interference on the cell viability, cell apoptosis, cell cycle, and tumor growth in nude mice were analyzed. Methods: We utilized pancreatic cancer cell lines that knocked down GINS2 expression using small interference RNA (siRNA) and evaluated GINS2 expression using Western blot analysis. To explore the function of GINS2 in pancreatic cancer cell lines in vitro, MTT assay and flow cytometry were used. Additionally, we investigated the potential mechanism of GINS2 interference by identifying the MAPK/ERK pathway using Western blotting. Finally, PANC-1 cells with GINS2 knockdown were subcutaneously injected into nude mice to evaluate the effects of GINS2 on tumor growth in vivo. Results: It was unveiled that GINS2 interference inhibited cell viability, induced cell cycle arrest at G1 phase, and enhanced apoptosis of pancreatic cancer cell lines. Western blot assay indicated that GINS2 interference increased the expression level of Bax, while the expression level of Bcl-2 was remarkably decreased. In addition, the expression levels of CDK4, CDK6, and Cyclin D1 were significantly reduced after treatment with GINS2 siRNA. Furthermore, GINS2 interference drastically attenuated the expression levels of MEK, p-MEK, ERK, and pERK , belonging to the MAPK/ERK pathway. The results of an established cancer xenograft model revealed that nude mice transplanted with cells expressing negative control (NC) exhibited larger and heavier tumors, while volume and weight of tumor were remarkably reduced in ones transplanted with cells expressing GINS2 siRNA. Conclusions: GINS2 interference inhibited cell viability, induced cell cycle arrest, and promoted cell apoptosis of pancreatic cancer cell lines via the MAPK/ERK pathway, and our findings may be valuable for treating pancreatic cancer.

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.