IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R

Chenyang Qiao,Meng Xie,Mengyu Sun,Xiaoyu Ji,Kaichun Wu,Danfei Liu,Tongyue Zhang,Yijun Wang,Daiming Fan,Jie Chen,Weibo Feng,Limin Xia,Wenjie Huang

doi:10.1038/s41419-021-03833-2

Abstract

Metastasis is the major reason for the high mortality of colorectal cancer (CRC) patients and its molecular mechanism remains unclear. Here, we report a novel role of Homeobox A13 (HOXA13), a member of the Homeobox (HOX) family, in promoting CRC metastasis. The elevated expression of HOXA13 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in two independent CRC cohorts. Overexpression of HOXA13 promoted CRC metastasis whereas downregulation of HOXA13 suppressed CRC metastasis. Mechanistically, HOXA13 facilitated CRC metastasis by transactivating ATP-citrate lyase (ACLY) and insulin-like growth factor 1 receptor (IGF1R). Knockdown of ACLY and IGFIR inhibited HOXA13-medicated CRC metastasis, whereas ectopic overexpression of ACLY and IGFIR rescued the decreased CRC metastasis induced by HOXA13 knockdown. Furthermore, Insulin-like growth factor 1 (IGF1), the ligand of IGF1R, upregulated HOXA13 expression through the PI3K/AKT/HIF1α pathway. Knockdown of HOXA13 decreased IGF1-mediated CRC metastasis. In addition, the combined treatment of ACLY inhibitor ETC-1002 and IGF1R inhibitor Linsitinib dramatically suppressed HOXA13-mediated CRC metastasis. In conclusion, HOXA13 is a prognostic biomarker in CRC patients. Targeting the IGF1-HOXA13-IGF1R positive feedback loop may provide a potential therapeutic strategy for the treatment of HOXA13-driven CRC metastasis.

Highlights

Metastasis is the main reason for the high mortality rate in patients with colorectal cancer (CRC)[1]
Homeobox A13 (HOXA13) is critical for Insulin-like growth factor 1 (IGF1)-induced CRC metastasis In view of the upregulated expression of HOXA13 treated by IGF1 and the pivotal role of HOXA13 in promoting CRC metastasis, we subsequently explored whether HOXA13 was involved in IGF1-mediated CRC metastasis
(see figure on previous page) Fig. 4 HOXA13 is critical for IGF1-induced CRC metastasis

Summary

Introduction

Metastasis is the main reason for the high mortality rate in patients with colorectal cancer (CRC)[1]. HOXA subfamily, one cluster of HOX genes, comprises 11 members and behaves as both oncogenic transcriptional factors and tumor suppressor genes (TSGs) exerting. HOXA15, HOXA26, HOXA77, HOXA98, HOXA109, HOXA1110, and HOXA1311 expression were elevated in several cancers and functioned as oncogenes to promote cancer invasion and metastasis. Several studies have reported that HOXA13, a member of the HOXA subfamily, was significantly elevated in several cancers, and was associated with TNM stage, lymph nodes metastasis, and unfavorable clinical outcome in ovarian cancer[14], pancreatic cancer[15], and bladder cancer[16]. A recent study reported that elevated HOXA13 expression was associated with histological grade, T stage, N stage, and tumor size in CRC tissues. In vitro studies showed that HOXA13 promoted colon cancer cell proliferation, migration, and invasion, and in vivo studies showed that HOXA13 promoted tumor formation through the Wnt/β-Catenin pathway[19].

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Results

Conclusion