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

Abstract

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.

Homeobox A7 promotes esophageal squamous cell carcinoma progression through C‐C motif chemokine ligand 2‐mediated tumor‐associated macrophage recruitment

“…HOXA7 has been reported to be responsible for upregulating chemokines to draw myeloid-derived immune suppressive cells into the TME. 29 Consistently, our results found that HOXA7 recruits TAMs through upregulation of CCL2, which has been reported to shape macrophage polarization under the influence of macrophage colony-stimulating factor 34 and promotes TAM recruitment through its receptor CCR2. 35 Our results showed that knockdown of HOXA7 significantly attenuated CCL2 secretion instead of other CCLs, thus inhibiting TAM infiltration and polarization.…”

“…Tumor‐associated macrophages exert immunosuppressive effects on tumor‐infiltrating lymphocytes and secrete anti‐inflammatory cytokines and chemokines including Arg1, 31 interleukin‐10, 32 and TGF‐β, 33 which strongly contribute to tumor proliferation and migration. HOXA7 has been reported to be responsible for upregulating chemokines to draw myeloid‐derived immune suppressive cells into the TME 29 . Consistently, our results found that HOXA7 recruits TAMs through upregulation of CCL2, which has been reported to shape macrophage polarization under the influence of macrophage colony‐stimulating factor 34 and promotes TAM recruitment through its receptor CCR2 35 .…”

“…The family of homeodomain‐containing transcription factors are known to be key regulators of embryonic development 28 . Moreover, the HOXA family has been reported to be associated with TME and the cross‐talk with tumor cells 9,29 . However, the functions of HOXA genes in ESCC remains largely unknown.…”

Impact of KRAS Mutation on Survival Outcome of Patients With Metastatic Colorectal Cancer in Jordan

“…Constitutive-activated KRAS mutation results from a point mutation most commonly seen in codons 12 and 13 in CRC, increasing the risk of cancer development and causing cancer cells, if formed, to proliferate uncontrollably and metastasize in the body [ 7 ]. It is estimated that 30-50% of CRC patients harbor the mutated KRAS gene form [ 8 ]. These mutations are strongly associated with resistance to anti-EGFR therapy, such as cetuximab and panitumumab.…”

Comprehensive analysis of a homeobox family gene signature in clear cell renal cell carcinoma with regard to prognosis and immune significance

“…The downregulated expression of HOXA7 in ccRCC and its lower expression being associated with poorer patients' prognosis indicated that it might be a tumor suppressor in ccRCC. However, HOXA7 was recently more reported to be oncogene and promoted oncogenic characteristics in many kinds of tumors such as liver cancer, cervical cancer, ovarian cancer, colorectal cancer and breast cancer (65)(66)(67)(68)(69). The role of HOXA7 in ccRCC had not been reported until now and exploring its effect on malignant characteristics of ccRCC might lead to the understanding of its diverse biological role and the complicated intracellular regulatory network.…”