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/HIF1 alpha 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.
基金：
National Natural Science Foundation of China [81772623, 81972237, 81871911, 81627807]; National Key Research and Development Program of China [2018YFC1312103, SQ2017YFSF090132]; National Center for Clinical Research of Digestive Diseases [2015BAI13B07]
第一作者单位：[1]Fourth Mil Med Univ, Natl Clin Res Ctr Digest Dis, State Key Lab Canc Biol, Xian 710032, Shaanxi, Peoples R China[2]Fourth Mil Med Univ, Xijing Hosp Digest Dis, Xian 710032, Shaanxi, Peoples R China
通讯作者：
通讯机构：[1]Fourth Mil Med Univ, Natl Clin Res Ctr Digest Dis, State Key Lab Canc Biol, Xian 710032, Shaanxi, Peoples R China[2]Fourth Mil Med Univ, Xijing Hosp Digest Dis, Xian 710032, Shaanxi, Peoples R China
推荐引用方式(GB/T 7714)：
Qiao Chenyang,Huang Wenjie,Chen Jie,et al.IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R[J].CELL DEATH & DISEASE.2021,12(6):doi:10.1038/s41419-021-03833-2.
APA：
Qiao, Chenyang,Huang, Wenjie,Chen, Jie,Feng, Weibo,Zhang, Tongyue...&Xia, Limin.(2021).IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R.CELL DEATH & DISEASE,12,(6)
MLA：
Qiao, Chenyang,et al."IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R".CELL DEATH & DISEASE 12..6(2021)
生物学