Tumor-associated macrophages improve hypoxia-induced endoplasmic reticulum stress response in colorectal cancer cells by regulating TGF-β1/SOX4

Hypoxia is a common feature of solid tumors that can induce endoplasmic reticulum stress (ERS). This study aimed to explore the mechanism behind tumor-associated macrophages (TAMs) improving the ERS response of colorectal cancer (CRC) under hypoxic conditions. Herein, it was demonstrated that TAMs reduce ERS by secreting TGF-β1 and activating SOX4/TMEM2 signaling in CRC cells. The expression levels of TGF-β1, SOX4, and TMEM2 in 20 pairs of tumor tissues and para-carcinoma tissues were assessed. A co-culture system of CRC cells with THP-1-derived macrophages under hypoxic conditions in vitro was investigated to determine the protective effect of TAMs on CRC cells. Moreover, to further verify the underlying mechanism, TGF-β1 and SOX4 were knocked down in the TAMs and CRC cells, respectively. The results exposed that TGF-β1, SOX4, and TMEM2 were abundantly expressed in tumor tissues. Moreover, the co-culture system revealed that macrophages stimulate TGF-β1 secretion under hypoxia, which depresses the CRC cells' ERS, further promoting cell proliferation and inhibiting apoptosis. Furthermore, increased TGF-β1 levels promoted the expression of SOX4 and TMEM2 in CRC cells. Conversely, the knockdown of SOX4 attenuated the protective effect of TAMs on TGF-β1-stimulated CRC cells. In conclusion, these results suggest that the elevated ERS induced by hypoxia in CRC cells could be relieved by TAMs via the secretion of TGF-β1. Finally, TGF-β1 suppresses undue ERS response in CRC cells by activating the SOX4-TMEM2 axis.