E3 Ubiquitin Ligase MARCH8 Promotes Pancreatic Cancer Growth and Metastasis by Activating STAT3 via Degradation of PTPN4

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Abstract
Objective: The role E3 ubiquitin ligase membrane-associated RING-CH 8 (MARCH8) has not been studied in pancreatic cancer. Method: Pancreatic cancer cell lines and the normal pancreatic cells were tested in vitro studies and male athymic nude mice were tested in vivo studies. Measuring cell viability by Cell Counting Kit-8 assay (CCK8), 5-ethynyl-2′- deoxyuridine (Edu) staining, and colony formation assay. Wound healing assay was implemented for cell migration and Transwell assay was performed for cell invasion to evaluate the histological status by hematoxylin and eosin staining and to detect the protein ubiquitination by ubiquitination assay. The protein expression was determined by immunohistochemistry staining and western blotting, and mRNA expression was measured by quantitative reverse transcription polymerase chain reaction. Result: The expression of MARCH8 was increased whereas PTPN4 was decreased in pancreatic cancer cells. Overexpression of MARCH8 promoted the growth, migration, and invasion of cells, and knockdown of PTPN4 had the similar effects both in vitro and in vivo. MARCH8 promoted PTPN4 protein degradation through ubiquitination. Moreover, PTPN4 suppressed the transcription activities of STAT3 by impairing the level of pSTAT3 (705), while inhibition of PTPN4 activated phosphorylation of STAT3. Conclusions: MARCH8 promoted pancreatic cancer growth and invasion through mediating the degradation of PTPN4 and activated the phosphorylation of STAT3.

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