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ZC3HAV1 promotes the proliferation and metastasis via regulating KRAS in pancreatic cancer.

ABSTRACT: Proliferation and metastasis are important malignant features of pancreatic cancer (PC), but the underlying molecular mechanism is unclear. ZC3HAV1, a PARP family member of proteins-enzymes, has been considered to play a significant part in a variety of biological processes. Nonetheless, the functions of ZC3HAV1 in developing PC are still unknown. This research aims to explore the biological function and the expression of ZC3HAV1 shown in PC. In our study, PCR analysis suggested that ZC3HAV1 was expressed at a high level in PC tissues and cell lines, and high ZC3HAV1 expression was remarkably related to poor prognosis. The functional assays indicated that upregulated ZC3HAV1 accelerated PC cell proliferation along with colony formation capacities in vitro. Subsequently, ZC3HAV1 could upregulate cyclin D1 and CDK2 and also promote G1/S transition in cells of PC. What's more, we also discovered that ZC3HAV1 promotes the migration and the invasion of PC cells. It upregulates the expression of EMT (epithelial-mesenchymal transition) relevant markers. Conversely, the functional assays showed that ZC3HAV1 knockdown significantly reduced tumorigenesis. Using bioinformatics analysis and immunoprecipitation assays we found that ZC3HAV1 could directly bind to KRAS and positively regulate its expression. Furthermore, ZC3HAV1 overexpression activated MAPK signaling by increasing p-ERK levels. Conversely, knockdown of KRAS attenuated ZC3HAV1-mediated promotion of proliferation and invasion in cells of PC. The result indicated that ZC3HAV1 was in relation to poor prognosis and accelerated the proliferation and metastasis of PC cells by regulation of KRAS. Our research may offer brand-new evidence to diagnose and treat PC in clinic.

SUBMITTER: Huang W

PROVIDER: S-EPMC8351712 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Exogenous HMGB1 plays a vital role in tumor recurrence, and HMGB1 is ubiquitous in the tumor microenvironment. However, the mechanism of action is still unclear. We investigated the role of exogenous HMGB1 in tumor proliferation and metastasis using human SW1990 and PANC-1 cells after radiotherapy and explored the possible molecular mechanism. Materials and Methods: Residual PANC-1 cells and SW1990 cells were isolated after radiotherapy. The supernatant after radiotherapy was collected. The relative expression of HMGB1 was evaluated by Enzyme Linked Immunosorbent Assay (ELISA). Electron microscope (EMS) was used to collect the images of pancreatic cancer cells pre and post radiotherapy treatment. The proliferation of pancreatic cancer cells which were treated with different radiation doses was measured by Carboxy Fluorescein Succinimidyl Ester (CFSE). The migration rates of pancreatic cancer cells were measured by wound healing assays. Subsequently, the expression of related proteins was detected by Western Blot. In vivo, the subcutaneous pancreatic tumor models of nude mice were established, and therapeutic capabilities were tested. Results: HMGB1 was detected in the supernatant of pancreatic cancer cells after radiotherapy. The results of CFSE showed that exogenous HMGB1 promotes the proliferation and metastasis of pancreatic cancer cells. The western blot results showed activation of p-GSK 3β and up-regulation of N-CA, Bcl-2, and Ki67 in response to HMGB1 stimulation, while E-CA expression was down-regulated in pancreatic cancer cells in response to HMGB1 stimulation. In vivo, ethyl pyruvate (EP, HMGB1 inhibitor) inhibits the growth of tumors and HMGB1 promotes the proliferation of tumors after radiation. Conclusion: Radiotherapy induces HMGB1 release into the extracellular space. Exogenous HMGB1 promotes the proliferation and metastasis of PANC-1 cells and SW1990 cells by activation of p-GSK 3β which is mediated by Wnt pathway.

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ZC3HAV1 promotes the proliferation and metastasis via regulating KRAS in pancreatic cancer.

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