IL25 Enhanced Colitis-Associated Tumorigenesis in Mice by Upregulating Transcription Factor GLI1.

Junxi Liu,Yandan Tan,Zewei Zhao,Siqi Liu,Ti Zhou,Xia Yang,Guoquan Gao,Zhonghan Yang,Gang Shen,Weiwei Qi,Jianglin Shi,Lin Zhou,Bingxiu Qian

doi:10.3389/fimmu.2022.837262

Abstract

Interleukin-25 (IL17E/IL25) plays a critical role in colitis and intestinal homeostasis. However, the expression and biological role of IL25 in colorectal cancer is not properly understood. In this study, we show that IL25 is mainly expressed by cancer stem cells in the colorectal cancer microenvironment. Genetic deletion of IL25 inhibited tumor formation and growth and prolonged survival in AOM/DSS-treated mice. IL25 stimulated cancer organoid and cancer cells sphere formation and prevented the tumor from chemotherapy-induced apoptosis. Mechanistically, IL25 upregulated stem cell genes LGR5, CD133, and ABC transporters via activating the Hedgehog signaling pathway. IL25 inhibited phosphorylation of AMPK and promoted GLI1 accumulation to maintain cancer stem cells. Moreover, IL25 expression was associated with poor survival in patients with metastatic colorectal cancer. Taken together, our work reveals an immune-associated mechanism that intrinsically confers cancer cell stemness properties. Our results first demonstrated that IL25, as a new potent endogenous Hedgehog pathway agonist, could be an important prognostic factor and therapeutic target for CRC.

Highlights

Colorectal cancer (CRC) is the third most occurring malignancy and the third most common cause of cancer death worldwide [1]
We retrospectively studied the medical records of 123 CRC patients and identified that IL25 expression increased along with the progression of CRC clinical stages (Figure 1C)
Through gene set enrichment analysis (GSEA) gene enrichment analysis, we found that ABCC2 and ABCC5 were significantly increased in IL25-high CRC and had a positive correlation with IL25 (Figures S1C, D)

Summary

Introduction

Colorectal cancer (CRC) is the third most occurring malignancy and the third most common cause of cancer death worldwide [1]. As the third-generation platinum drug, oxaliplatin is the first-line treatment for patients with metastatic colorectal cancer (mCRC) [2]. The 5-year survival rates for patients with metastasis are approximately 14% [3, 4]. One of the major reasons for treatment failure and poor prognosis is drug resistance [5]. It is essential for us to clarify the mechanism of chemotherapy resistance and to develop approaches to prevent or reverse drug resistance for patients with mCRC. Cancer stem cells (CSCs) play a major role in tumor growth, progression and can resist chemotherapeutic agents by increasing drug efflux ABC transporters and activating DNA repair

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