Abstract
BackgroundKRAS 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.MethodsThe 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.ResultsElevated 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.ConclusionsHOXA7 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.
Highlights
Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer-related death in the world [1]
Elevated Homeobox A7 (HOXA7) positively correlates with poor prognosis in colorectal cancer (CRC) patients harboring KRAS mutation To characterize the function of HOXA7 in CRC, we examined its mRNA expression in 20 normal colorectal epithelial specimens and 100 paired CRC and adjacent nontumor specimens
We found that CRC tissues exhibited higher HOXA7 mRNA levels than paired nontumor tissues and normal colorectal epithelial tissues (Fig. 1A, left)
Summary
Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer-related death in the world [1]. KRAS mutation is associated with disease aggressiveness and metastasis and appears in 30–50% of human CRC patients [2, 3]. KRASG12C specific inhibitor, covalently binds to a pocket of the switch II region of K RASG12C which is present only in the inactive GDP-bound conformation. The effective rate in patients with CRC with the KRASG12C mutation is poor [8], and the underlying mechanism is unclear. KRAS mutation accounts for 30–50% of human colorectal cancer (CRC) cases. Metastasis is still the major cause of the high mortality associated with KRAS mutant CRC, but the exact mechanism remains unclear. 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
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