Colorectal cancer prompted adipose tissue browning and cancer cachexia through transferring exosomal miR‐146b‐5p

Abstract

Cancer cachexia is a complex syndrome that is associated with thermogenic gene regulation. Currently, although some studies have reported the link between exosomes and cancer cachexia in a few types of cancer, the underlying mechanisms remain poorly understood. In this study, we tried to identify whether exosomes derived from colorectal cancer could affect lipolysis in vitro and in vivo. Here, we collected the tissue samples from 48 patients with colorectal cancer (47.91% females and mean age 55 ± 8.20) and 48 healthy people at the First Affiliated Hospital of Nanjing Medical University to detect the miR‐146‐5p expression. Here, we found that cancer cells released exosomes induced white adipose tissues (WATs) browning and accelerated lipolysis. We also demonstrated that miR‐146b‐5p was enriched in cancer‐related exosomes. Overexpression miR‐146b‐5p resulted in increased WAT browning, decreased oxygen consumption, and fat mass loss (14.57%). The further study identified that miR‐146b‐5p could directly repress the downstream gene homeodomain‐containing gene C10 (HOXC10), thereby regulating lipolysis. Therefore, our results indicated that cancer cells derived from exosomal miR‐146b‐5p played an essential role in WAT browning. Inhibition of cancer‐related exosomes might be necessary for improving the cachexia condition.

Role of HOXC10 in Cancer

“…We also provided a comprehensive description of HOXC10 expression regulation. Specifically, HOXC10 expression is regulated by several epigenetic processes, including DNA ( 6 , 50 , 96 ) and histone ( 5 , 97 ) methylation, posttranscriptional miRNA ( 10 – 12 , 59 , 61 , 64 , 98 ) and lncRNA ( 9 , 99 ) modifications, and ubiquitin modifications ( 100 ).…”

“…MicroRNAs (miRNAs) are small noncoding RNAs that can degrade or suppress the translation of target mRNAs by base pairing with the 3’-untranslated region (3’UTR) ( 106 ). Several miRNAs, such as miR-129-5p ( 10 – 12 ), miR-222-3p ( 64 ), miR-146b-5p ( 98 ), miRNA-221 ( 61 ), and miRNA-136 ( 59 ), have been reported to play a key role in regulating HOXC10 expression. These miRNAs directly target the 3’UTR of HOXC10 to inhibit HOXC10 expression.…”

Cancer-Associated Fibroblasts Influence the Biological Properties of Malignant Tumours via Paracrine Secretion and Exosome Production

“…Similarly, structural and functional changes of white adipose tissue were observed in cachectic patients. This browning of adipose tissue may be linked to the effect of miR-146b-5p carried in exosomes [165]. This insidious syndrome dramatically impacts the quality of the remainder of the patient's life, but is also associated with poor responses to therapy and decreased survival [166].…”

Lipid Metabolism Interplay in CRC—An Update

“…Beside low food intake, adipose tissue dysfunction is a major player in cancer cachexia, during which white adipose tissue (WAT) is undergoing a browning process marked by increased lipid mobilization and energy expenditure [ 134 ]. Exosomal miR-146-5p derived from CRC cells could induce WAT browning and lipolysis, through repression of homeodomain-containing gene C10 (HOXC10), illustrating the importance of cell crosstalk in the tumor microenvironment [ 135 ]. Interestingly, in a pre-clinical model of CRC, it was shown that chemotherapy treatment decreased the size of adipocytes and also the expression of proteins involved in ATP production, β-oxidation and lipogenesis [ 136 ].…”