HOXA7 promotes the metastasis of KRAS mutant colorectal cancer by regulating myeloid-derived suppressor cells

Background KRAS mutation accounts for 30-50% of human colorectal cancer (CRC) cases. Due to the scarcity of effective treatment options, KRAS mutant CRC is difficult to treat in the clinic. Metastasis is still the major cause of the high mortality associated with KRAS mutant CRC, but the exact mechanism remains unclear. Here, we report a unique function of Homeobox 7 (HOXA7) in driving KRAS mutant CRC metastasis and explore therapeutic strategies for subpopulations of patients with this disease. Methods The expression of HOXA7 in a human CRC cohort was measured by immunohistochemistry. The function of HOXA7 in KRAS mutant CRC metastasis was analyzed with the cecum orthotopic model. Results Elevated HOXA7 expression was positively correlated with lymph node metastasis, distant metastasis, poor tumor differentiation, high TNM stage, and poor prognosis in CRC patients. Furthermore, HOXA7 was an independent prognostic marker in KRAS mutant CRC patients (P < 0.001) but not in KRAS wild-type CRC patients (P = 0.575). Overexpression of HOXA7 improved the ability of KRAS mutant CT26 cells to metastasize and simultaneously promoted the infiltration of myeloid-derived suppressor cells (MDSCs). When MDSC infiltration was blocked by a CXCR2 inhibitor, the metastasis rate of CT26 cells was markedly suppressed. The combination of the CXCR2 inhibitor SB265610 and programmed death-ligand 1 antibody (anti-PD-L1) could largely inhibit the metastasis of KRAS mutant CRC. Conclusions HOXA7 overexpression upregulated CXCL1 expression, which promoted MDSC infiltration. Interruption of this loop might provide a promising treatment strategy for HOXA7-mediated KRAS mutant CRC metastasis.

Automated summary

This study reveals that elevated expression of HOXA7 is associated with metastasis and poor prognosis in KRAS mutant colorectal cancer (CRC) patients. HOXA7 overexpression enhances the metastatic ability of KRAS mutant cells and promotes the infiltration of myeloid-derived suppressor cells (MDSCs). Furthermore, blocking MDSC infiltration can effectively suppress the metastasis of KRAS mutant CRC. Therefore, interrupting the HOXA7-mediated loop may provide a promising strategy for the treatment of this disease.