Theranostics 2021; 11(6):2612-2633. doi:10.7150/thno.52199

Research Paper

CXCL12-mediated HOXB5 overexpression facilitates Colorectal Cancer metastasis through transactivating CXCR4 and ITGB3

Weibo Feng1#, Wenjie Huang2,3#, Jie Chen1#, Chenyang Qiao1#, Danfei Liu2, Xiaoyu Ji2, Meng Xie2, Tongyue Zhang2, Yijun Wang2, Mengyu Sun2, Dean Tian2, Daiming Fan1, Yongzhan Nie1, Kaichun Wu1✉, Limin Xia1,2✉

1. State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
2. Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
3. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Clinical Medicine Research Center for Hepatic Surgery of Hubei Province; Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei, 430030, China.
#These authors contributed equally to this work.

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Citation:
Feng W, Huang W, Chen J, Qiao C, Liu D, Ji X, Xie M, Zhang T, Wang Y, Sun M, Tian D, Fan D, Nie Y, Wu K, Xia L. CXCL12-mediated HOXB5 overexpression facilitates Colorectal Cancer metastasis through transactivating CXCR4 and ITGB3. Theranostics 2021; 11(6):2612-2633. doi:10.7150/thno.52199. Available from https://www.thno.org/v11p2612.htm

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Abstract

Background: Metastasis is the major reason for the high mortality of colorectal cancer (CRC). However, the molecular mechanism underlying CRC metastasis remains unclear. Here, we report a novel role of homeobox B5 (HOXB5), a member of the HOX family, in promoting CRC metastasis.

Method: The expression of HOXB5 and its target genes were examined by immunohistochemistry in human CRC. Chromatin immunoprecipitation and luciferase reporter assays were performed to measure the transcriptional regulation of target genes by HOXB5. The metastatic capacities of CRC cells were evaluated by in vivo lung and liver metastatic models.

Results: The elevated expression of HOXB5 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in CRC patients. HOXB5 expression was an independent and significant risk factor for the recurrence and survival in CRC patients. Overexpression of HOXB5 promoted CRC metastasis by transactivating metastatic related genes, C-X-C motif chemokine receptor 4 (CXCR4) and integrin subunit beta 3 (ITGB3). C-X-C motif chemokine ligand 12 (CXCL12), which is the ligand of CXCR4, upregulated HOXB5 expression through the extracellular regulated protein kinase (ERK)/ETS proto-oncogene 1, transcription factor (ETS1) pathway. The knockdown of HOXB5 decreased CXCL12-enhanced CRC metastasis. Furthermore, AMD3100, a specific CXCR4 inhibitor, significantly suppressed HOXB5-mediated CRC metastasis. HOXB5 expression was positively correlated with CXCR4 and ITGB3 expression in human CRC tissues, and patients with positive co-expression of HOXB5/CXCR4, or HOXB5/ITGB3 exhibited the worst prognosis.

Conclusion: Our study implicates HOXB5 as a prognostic biomarker in CRC, and defines a CXCL12-HOXB5-CXCR4 positive feedback loop that plays an important role in promoting CRC metastasis.

Keywords: homeobox B5, colorectal cancer, metastasis, C-X-C motif chemokine receptor 4, AMD3100