Pancreatic cancer is one of the most aggressive cancers worldwide with a high mortality rate. Prognosis remains poor even in this era of advanced medicine mainly due to early metastasis and invasion. The present study aimed to explore and validate predictors of distant metastasis and prognosis in pancreatic cancer. In our preliminary experiment, we established a novel metastatic pancreatic cancer cell line BxPC-M8 from parent BxPC-3 cells. Via whole genome sequencing, RT-qPCR, western blotting, migration and invasion assays, we initially found that BxPC-M8 shared similar biological characteristics to BxPC-3, but only differed in enhanced metastatic and invasive capabilities with a significant increase in collagen type VI α1 chain (COL6A1) expression. Knockdown of COL6A1 via small interfering RNA led to a significant decrease in migration and invasion of BxPC-M8 cells, suggesting suppressed epithelial-mesenchymal transition. Furthermore, a significant increase in COL6A1 expression was observed in cancerous tissue compared with paracancerous tissue (40.7 vs 3.7, P=0.001). Additionally, its expression was observed to be significantly associated with distant metastasis and vascular invasion at the time of surgery. Multivariate analysis revealed that COL6A1 expression (hazard ratio 1.90, 95% confidence interval 1.04-3.47, P=0.037) is an independent predictor of overall survival (OS). The median OS observed for COL6A1 + and COL6A1patients was found to be 8±4 and 14±7 months (P= 0.021), respectively. Of note, we identified that COL6A1 expression in tissue samples was associated with significantly reduced OS (P= 0.001), demonstrating that COL6A1 may serve an important role in the metastatic process and could be considered as a predictor of poor outcomes in patients with pancreatic cancer. In addition, our findings suggest that COL6A1 could be an indicator of distant metastasis and a valid prognostic predictor in such patients; however, further investigation is required.
Cell division cycle associated 5 (CDCA5) is an important element for the interaction between cohesin and chromatin in interphase. It is abnormally expressed in many types of cancer and works as an indicator of poor prognosis, but little is known about its activity in hepatocellular carcinoma (HCC). In the present study, we found that the expression of CDCA5 was upregulated in HCC tissues compared to paracancerous tissues and had a negative correlation with patient survival. Cell proliferation and tumorigenesis were inhibited and cell apoptosis was induced with the knockdown of CDCA5, suggesting an oncogenic role of CDCA5 in liver cancer. Luciferase reporter assay and chromatin immunoprecipitation showed that CDCA5 was transcribed by E2F1. Furthermore, we confirmed that CDCA5 interrupted cell behavior via the AKT pathway. These findings demonstrated that CDCA5 plays an important role in HCC progression.
ERBB4 is one of the members of the epidermal growth factor receptor (EGFR) family. ERBB4 is a large transmembrane glycoprotein and has tyrosine kinase activity. Once combined with epidermal growth factor (EGF), ERBB4 can activate the related genes in the nucleus, thus promoting cell division and proliferation. In the present study, we investigated the effect of ERBB4 in the proliferation of gastric cancer cells. We found that high ERBB4 levels were closely related to the poor prognosis of gastric cancer patients. Furthermore, ERBB4 was highly expressed in gastric cancer cell lines when compared to the normal stomach cell line, GES. Clinical samples provided the same results. Two gastric cancer cell lines, SGC‑7901 and MNK‑45 were used to study the underlying mechanism of ERBB4 in the promotion of cell proliferation in gastric cancer cells both in vitro and in vivo. It was observed that after the expression of ERBB4 was suppressed, the proliferation of gastric cancer cells was markedly inhibited both in vitro and in vivo. Moreover, treatment with lentiviral vector siRNA‑ERBB4 (Lv‑siRNA‑ERBB4) or the ERBB4 inhibitor AST‑1306, markedly inhibited gastric cancer cell proliferation. Further experiments revealed that inhibition of the expression of ERBB4 could inhibit the activation of the PI3K/Akt signaling pathway. In addition, the use of the PI3K/Akt signaling pathway inhibitor LY294002 demonstrated the aforementioned results. Therefore, we believe that ERBB4 regulates cell proliferation mainly through the PI3K signaling pathway. Finally, nude mice xenografted with gastric cancer cells with low expression of ERBB4 exhibited smaller tumors and longer survival than those engrafted with control gastric cancer cells. These data indicated that ERBB4 promoted cell proliferation and is thus a potential therapeutic target for the treatment of gastric cancer.
Epithelial-mesenchymal transition (EMT) is an important biological process that is characteristic of malignant tumor cells with metastatic potential. We investigated the role of miR-551b in EMT and metastasis in gastric cancer (GC). We found that low miR-551b levels were associated with EMT, metastasis and a poor prognosis in GC patients. Further, two GC cell lines, MNK45 and SGC7901, exhibited lower miR-551b levels than the GES normal stomach cell line. Exposing MNK45 and SGC7901 cells to TGF-β1 resulted in cell morphology changes characteristic of EMT, which was confirmed by Western blot analysis demonstrating low E-Cadherin and high N-Cadherin and Vimentin levels. Treatment with miR-551b mimics inhibited these EMT changes as well as Transwell migration and invasiveness. We identified ERBB4 as a potential target of miR-551b based on patient data from the TCGA. ERBB4 was upregulated in GC specimens, and its high expression correlated with a poor prognosis of GC patients. Dual luciferase assays revealed that miR-551b directly inhibited ERBB4 by binding to its 3′UTR. Moreover, treatment with miR-551b mimics or the ERBB4 inhibitor AST-1306 inhibited EMT in the GC cell lines. Finally, nude mice xenografted with GC cancer cell lines expressing miR-551b mimics exhibited smaller tumors and longer survival than mice engrafted with control GC cancer cells. These data indicate that miR-551b inhibits EMT and metastasis in GC by inhibiting ERBB4. miR-551b and ERBB4 are thus potential therapeutic targets for the treatment of GC.
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