Jing Ni

P4HB promotes HCC tumorigenesis through downregulation of GRP78 and subsequent upregulation of epithelial-to-mesenchymal transition

P4HB and GRP78 are molecular chaperones involved in cellular response to ER stress. They have been linked to cancer progression; however, their roles in hepatocellular carcinoma (HCC) are largely unclear. In this study, we found that P4HB is overexpressed in human HCC tissues and cell lines. Higher tumoral P4HB levels are correlated with more advanced disease and poorer survival. GRP78 expression is inversely correlated with P4HB in human HCC tissues, and downregulated by P4HB in HCC cell lines. P4HB overexpression promotes HCC cell growth, migration, invasion and epithelial-to-mesenchymal transition (EMT) in vitro. GRP78 overexpression not only inhibits HCC cell growth, migration, invasion and EMT, but also antagonizes the oncogenic effects of P4HB overexpression. Furthermore, P4HB silencing inhibits HCC tumorigenesis in vivo. Taken together, our results provided evidence that P4HB promotes HCC progression through downregulation of GRP78 and subsequent upregulation of EMT.

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.

Anticancer effects of echinacoside in hepatocellular carcinoma mouse model and HepG2 cells: YE et al.

Echinacoside (ECH) is a phenylethanoid glycoside extracted from a Chinese herbal medicine, Cistanches salsa. ECH possesses many biological properties, including anti‐inflammation, neural protection, liver protection, and antitumor. In the current study, we aimed to explore the effects of ECH on hepatocellular carcinoma (HCC) and the underlying mechanisms. The results showed that ECH could attenuate diethylnitrosamine (DEN)‐induced HCC in mice, and exerted antiproliferative and proapoptotic functions on HepG2 HCC cell line. ECH exposure in HepG2 cells dose‐dependently reduced the phosphorylation of AKT (p‐AKT) and enhanced the expression of p21 (a cell cycle inhibitor) and Bax (a proapoptotic protein). Furthermore, ECH significantly suppressed insulin‐like growth factor‐1‐induced p‐AKT and cell proliferation. These data indicated that phosphoinositide 3‐kinase (PI3K)/AKT signaling was involved in the anti‐HCC activity of ECH. Gene set enrichment analysis results revealed a positive correlation between the PI3K pathway and triggering receptors expressed on myeloid cells 2 (TREM2) expression in HCC tissues. ECH exposure significantly decreased TREM2 protein levels in HepG2 cells and DEN‐induced HCC. Furthermore, ECH‐mediated proliferation inhibition and AKT signaling inactivation were notably attenuated by TREM2 overexpression. In conclusion, ECH exerted its antitumor activity via decreasing TREM2 expression and PI3K/AKT signaling.

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.

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.

Application of the R0-R3 formulas using the ECToolbox software to calculate left ventricular ejection fraction in myocardial perfusion SPET and comparison with equilibrium radionuclide ventriculography. Normal cutoff values for a Chinese population

The aim of this study was to compare the correlation and consistency of left ventricular ejection fraction (LVEF) obtained by ECG-gated myocardial perfusion SPET (GMPS) using the four formulas (R0-R3) in ECToolbox software and by equilibrium radionuclide ventriculography (ERNV), and determine the optimal diagnostic thresholds of the four formulas in a Chinese population. A hundred and three candidate donors (59 male and 44 female), including 38 patients with a history of myocardial infarction and 65 patients with suspected coronary heart disease, underwent both (99m)Tc-MIBI rest GMPS and technetium-99m red blood cells ((99m)Tc-RBC) ERNV within a week. The LVEF values calculated by ECToolbox R0, R1, R2 and R3 were compared with those obtained by ERNV. Using LVEF≥50% obtained by ERNV as the gold standard, the optimal diagnostic thresholds of the four formulas (R0-R3) were assessed by receiver operating characteristic (ROC) curves. Results showed that the mean LVEF value of ERNV was 54.6±17.5%, and the mean LVEF value of the four formulas was 64.1±15.7%, 56.3±15.1%, 69.9±17.9% and 56.3±13.6%, respectively, showing a significantly strong correlation between the results obtained by the two methods (r>0.85, P<0.001). All mean LVEF values obtained by the four formulas were higher than the mean LVEF value obtained by ERNV, and there was very significant difference between R0 and R2 results and the ERNV result (t=12.511 and 18.652, P<0.001). Furthermore, there was significant difference between R1 and R3 results and the ERNV result (t=2.169 and 2.570, P<0.05). Using ERNV LVEF≥50% as the normal diagnostic value, the optimal diagnostic threshold of R0∼R3 was 56.5%, 51.5%, 64.5% and 52.5%, respectively. There was a strong correlation between the LVEF values obtained by the four formulas in ECToolbox software and ERNV, but the numerical values of LVEF differed between the four formulas. In conclusion, A strong correlation was observed among R0, R1, R2 and R3 in the ECToolbox software when compared with ERNV and also between them for the assessment of LVEF. However, there were some differences in the numerical values of LVEF generated by the individual formulas, which must be taken into account in comparing clinical studies.