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Research Paper|Volume 12, Issue 22|pp 22564—22581

Upregulated GDF-15 expression facilitates pancreatic ductal adenocarcinoma progression through orphan receptor GFRAL

Zhiping Zhao1, Junfeng Zhang1, Liangyu Yin1, Jiali Yang1, Yao Zheng1, Mengjie Zhang3, Bing Ni3, Huaizhi Wang1,2
  • 1Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, P. R. China
  • 2Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 400038, P. R. China
  • 3Department of Pathophysiology, College of High Altitude Military Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, P. R. China
Received: March 31, 2020Accepted: July 14, 2020Published: November 17, 2020
https://doi.org/10.18632/aging.103830

Copyright: © 2020 Zhao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Growth and differentiation factor 15 (GDF-15) has been studied as an important hallmark of cancer. However, the receptor of GDF-15 in pancreatic cancer cell remains unclear. Here, we investigated its biological effects in pancreatic ductal adenocarcinoma (PDAC). We found that aberrant GDF-15 expression positively correlated with poor survival of PDAC patients. GDF-15 protein enhanced tumor cell proliferation in two pancreatic cancer lines, AsPC-1 and BxPC-3. Knockdown GDF-15 attenuated its biological function in vitro and reduced PDAC cell tumorigenesis upon xenotransplantation into nude mice. Moreover, we identified that glial-derived neurotropic factor family receptor α-like (GFRAL) was upregulated in PDAC tissues and positively correlated with GDF-15 expression. High GFRAL expression was significantly associated with poor survival in PDAC patients. Furthermore, we identified that the biological effects of GDF-15 are mediated by its receptor GFRAL which is present in PDAC cells. After overexpression GFRAL in pancreatic cancer cells, the effect of GDF-15 was significantly enhanced. Overall, our findings demonstrated that the GDF-15 secreted by PDAC cells, binds to GFRAL, itself localized in PDAC cells, to promote cancer cell growth and metastasis through the GDF-15/GFRAL signaling pathway.