MIIP downregulation drives colorectal cancer progression through inducing peri-cancerous adipose tissue browning

Sep 21, 2026

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Peri-cancerous adipose tissue is a hallmark of colorectal cancer (CRC), accelerating progression and worsening prognosis, yet the regulatory mechanisms remain unclear. This study investigates how downregulation of the migration and invasion inhibitory protein (MIIP) remodels tumor cell–adipocyte communication and promotes CRC. MIIP reduction decreases in CRC and correlates with adjacent adipocyte browning, enhancing lipolysis and free-fatty-acid–driven tumor growth and therapy resistance via AZGP1 cAMP-PKA signaling and N-glycosylation.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages22

Reading Time55 min

AccessFree to download

Abstract

Background

Results

Conclusions

Keywords

Background

Peri-cancerous adipose tissue and WAT browning

Wang et al. Cell & Bioscience (2024) 14:12 [https://doi.org/10.1186/s13578-023-01179-0](https://doi.org/10.1186/s13578-023-01179-0) Cell & Bioscience RESEARCH Open Access MIIP downregulation drives colorectal cancer progression through inducing peri-cancerous adipose tissue browning Qinhao Wang1*†, Yuanyuan Su1,2†, Ruiqi Sun1,3†, Xin Xiong1, Kai Guo4, Mengying Wei1, Guodong Yang1, Yi Ru 1, Zhengxiang Zhang2, Jing Li5, Jing Zhang6, Qing Qiao7* and Xia Li 1* Abstract Background The enrichment of peri-cancerous adipose tissue is a distinctive feature of colorectal cancer (CRC), accelerating disease progression and worsening prognosis. The communication between tumor cells and adjacent adipocytes plays a crucial role in CRC advancement. However, the precise regulatory mechanisms are largely unknown. This study aims to explore the mechanism of migration and invasion inhibitory protein (MIIP) downregulation in the remodeling of tumor cell-adipocyte communication and its role in promoting CRC. Results MIIP expression was found to be decreased in CRC tissues and closely associated with adjacent adipocyte browning. In an in vitro co-culture model, adipocytes treated with MIIP-downregulated tumor supernatant exhibited aggravated browning and lipolysis. This finding was further confirmed in subcutaneously allografted mice co-injected with adipocytes and MIIP-downregulated murine CRC cells. Mechanistically, MIIP interacted with the critical lipid mobilization factor AZGP1 and regulated AZGP1’s glycosylation status by interfering with its association with STT3A. MIIP downregulation promoted N-glycosylation and over-secretion of AZGP1 in tumor cells. Subsequently, AZGP1 induced adipocyte browning and lipolysis through the cAMP-PKA pathway, releasing free fatty acids (FFAs) into the microenvironment. These FFAs served as the primary energy source, promoting CRC cell proliferation, invasion, and apoptosis resistance, accompanied by metabolic reprogramming. In a tumor-bearing mouse model, inhibition of β-adrenergic receptor or FFA uptake, combined with oxaliplatin, significantly improved therapeutic efficacy in CRC with abnormal MIIP expression. Conclusions Our data demonstrate that MIIP plays a regulatory role in the communication between CRC and neighboring adipose tissue by regulating AZGP1 N-glycosylation and secretion. MIIP reduction leads to AZGP1 oversecretion, resulting in adipose browning-induced CRC rapid progression and poor prognosis. Inhibition of β-adrenergic receptor or FFA uptake, combined with oxaliplatin, may represent a promising therapeutic strategy for CRC with aberrant MIIP expression. †Qinhao Wang, Yuanyuan Su and Ruiqi Sun have contributed equally to this work. *Correspondence: Qinhao Wang [bcmbwang@fmmu.edu.cn](bcmbwang@fmmu.edu.cn)[ ](bcmbwang@fmmu.edu.cn)Qing Qiao [qqing44@fmmu.edu.cn](qqing44@fmmu.edu.cn)[ ](qqing44@fmmu.edu.cn)Xia Li [lixia@fmmu.edu.cn](lixia@fmmu.edu.cn) Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedicat

FAQs

How does MIIP downregulation affect colorectal cancer progression?

MIIP expression decreases in CRC and is linked to adjacent adipocyte browning. In co-culture and mouse models, MIIP-downregulated tumor secretome worsens browning and lipolysis, promoting CRC proliferation, invasion, and apoptosis resistance.

What molecular pathway connects MIIP to adipocyte browning?

Mechanistically, MIIP interacts with AZGP1 and alters its glycosylation by disrupting AZGP1 association with STT3A. The resulting AZGP1 over-secretion triggers adipocyte browning and lipolysis through the cAMP-PKA pathway.

How might therapy be improved for CRC with abnormal MIIP expression?

In a tumor-bearing mouse model, combining β-adrenergic receptor inhibition or FFA uptake inhibition with oxaliplatin significantly improves therapeutic efficacy in CRC cases with abnormal MIIP expression.

Sep 21, 2026

Uploaded by Jiven