HSPB8 Induces 5-Fluorouracil Resistance in Colorectal Cancer by Promoting Tumor Autophagy

Abstract

The emergence of 5-Fluorouracil (5-FU) resistance is the barrier to effective clinical outcomes for CRC patients. Autophagy was found to be involved in protecting tumor cells from 5-FU. However, the specific role of autophagy-related genes in CRC 5-FU resistance remains unclear. In this study, HSPB8 among 34 differentially expressed ARGs in CRC was identified to be the hub ARGs in 5-FU resistant which was down-regulated in CRC samples when compared with normal samples but up-regulated in CRC samples with relatively higher lymphatic invasion, later stages and poor prognosis of CRC. Mechanistic analysis demonstrated that due to the recruitment of CAFs, HSPB8 expression was enhanced in CRC cells so that HSPB8 could act together with its co-chaperone BAG3 in autophagy drived 5-FU resistance. Furthermore, the augmented expression level of HSPB8 was found to be significantly correlated to the immune cell infiltration such as Treg cells, macrophages, monocyte and dendritic cells and so on. Our results suggested CAFs driving HSPB8 induced CRC 5-FU resistance by promoting tumor autophagy would provide a new strategy in seeking potential CRC therapeutic target. Funding Information: This project was supported by grants from New Testing Technology Center of Guangdong Experimental Animal Monitoring Institute. The National Nature Science Foundation of China (No. 81972806), Key Project of Science and Technology Development of Nanjing Medicine (ZDX16001) to SKW; The National Nature Science Foundation of China (No. 81802093) to HLS; The National Nature Science Foundation of China (No. 81903034) and the development of Nanjing medical science and technology foundation to Tianyi Gao (no. YKK17123). Declaration of Interests: The authors declare no competing interests.