SPHK1-induced autophagy in peritoneal mesothelial cell enhances gastric cancer peritoneal dissemination.

Songcheng Yin,Zhifeng Miao,Yuen Tan,Huimian Xu,Jinyu Huang,Pengliang Wang,Chao Zhang,Wenbin Hou,Xiaoyu Xu

doi:10.1002/cam4.2041

Abstract

Gastric cancer peritoneal dissemination (GCPD) has been recognized as the most common form of metastasis in advanced gastric cancer (GC), and the survival is pessimistic. The injury of mesothelial cells plays an important role in GCPD. However, its molecular mechanism is not entirely clear. Here, we focused on the sphingosine kinase 1 (SPHK1) in human peritoneal mesothelial cells (HPMCs) which regulates HPMCs autophagy in GCPD progression. Initially, we analyzed SPHK1 expression immunohistochemically in 120 GC peritoneal tissues, and found high SPHK1 expression to be significantly associated with LC3B expression and peritoneal recurrence, leading to poor prognosis. Using a coculture system, we observed that GC cells promoted HPMCs autophagy and this process was inhibited by blocking TGF‐β1 secreted from GC cells. Autophagic HPMCs induced adhesion and invasion of GC cells. We also confirmed that knockdown of SPHK1 expression in HPMCs inhibited TGF‐β1‐induced autophagy. In addition, SPHK1‐driven autophagy of HPMCs accelerated GC cells occurrence of GCPD in vitro and in vivo. Moreover, we explored the relationship between autophagy and fibrosis in HPMCs, observing that overexpression of SPHK1 induced HPMCs fibrosis, while the inhibition of autophagy weakened HPMCs fibrosis. Taken together, our results provided new insights for understanding the mechanisms of GCPD and established SPHK1 as a novel target for GCPD.

Highlights

Gastric cancer (GC) remains the fifth most frequent cancer and the third leading cause of cancer death worldwide in 2018.1 Gastrectomy‐based perioperative or postoperative adjuvant therapies have been applied, but prognosis remains unsatisfactory.[2]
We explored the relationship between autophagy and fibrosis in human peritoneal mesothelial cells (HPMCs), observing that the regulation of HPMCs fibrosis was partially induced by sphingosine kinase 1 (SPHK1)‐induced autophagy
By fluorescently examining the numbers of SGC‐7901 and MGC‐803 cells adhering to HPMCs, we found that the attachment of GC cells was significantly decreased for SGC‐7901‐shTGF‐β1‐cocultured and 3‐MA‐treated HPMCs compared with the findings for SGC‐7901‐shCtrl‐cocultured cells (Figure 3B)

Summary

| INTRODUCTION

Gastric cancer (GC) remains the fifth most frequent cancer and the third leading cause of cancer death worldwide in 2018.1 Gastrectomy‐based perioperative or postoperative adjuvant therapies have been applied, but prognosis remains unsatisfactory.[2]. Gastric cancer peritoneal dissemination (GCPD) is the result of interactions between tumor cells and the. HPMC fibrosis, as a critical mediator of GCPD, promoted tumor cell adhesion and invasion.[7]. SPHK1 plays an oncogenic role in promoting survival and invasion in some tumors.[14]. High SPHK1 expression promoted breast cancer cell proliferation and invasion, which were associated with poor overall survival.[15]. The precise roles of SPHK1 in HPMCs autophagy, in addition to the regulatory mechanisms and the relationship of SPHK1 with GCPD, should be confirmed. We found that overexpression of SPHK1 in HPMCs was associated with LC3B expression (an autophagy protein marker), peritoneal recurrence, and poor overall survival. We observed that GC cells secreted TGF‐β1, which promoted HPMCs autophagy by regulating SPHK1. We explored the relationship between autophagy and fibrosis in HPMCs, observing that the regulation of HPMCs fibrosis was partially induced by SPHK1‐induced autophagy

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION