MIIP downregulation promotes colorectal cancer progression via inducing adjacent adipocytes browning

Abstract

The enrichment of peri-cancerous adipocytes is one of the distinctive features of colorectal cancer (CRC), which accelerates the disease progression and worsens the prognosis. The communication between tumor cells and adjacent adipocytes plays an important role in this process. However, the detailed mechanisms remain largely unknown. Here we demonstrated MIIP is downregulated in high-grade CRC, and revealed its role and mechanism in tumor cell-adipocyte communication. By detecting MIIP expression in CRC tissues and adjacent normal tissues, we found MIIP was significantly decreased in CRC, and was closely related to adjacent adipocytes browning. In detail, MIIP reduction altered the N-linked glycosylation modification of AZGP1 and thus alleviated the inhibition of secretion. AZGP1, a critical lipid mobilization factor, led to the intensification of adipocytes browning and the release of free fatty acids (FFAs), which in turn fueled for CRC progression. Our data demonstrate that MIIP plays a key regulatory role in the communication between CRC and neighboring adipocytes by mediating AZGP1 secretion, and MIIP reduction leads to adipose browning-induced cancer rapid progression and poor prognosis.