Homeobox A1 Facilitates Immune Escape and Alleviates Oxidative Stress in Lung Adenocarcinoma

Abstract

Objective. Recent studies have demonstrated that homeobox A1 (HOXA1) is upregulated in lung cancer due to RNA modifications (N6-methyladenosine), but the specific function of HOXA1 in lung adenocarcinoma (LUAD) remains indistinct. Herein, we investigated the role of HOXA1 in LUAD biology. Methods. This study presented pancancer analysis of associations of HOXA1 with prognosis, TMB, and immune checkpoints. The expression of HOXA1 was detected in LUAD and normal tissues with immunohistochemistry and western blot. Through least absolute shrinkage and selection operator (LASSO) analysis, HOXA1-derived gene model was conducted in LUAD. Correlations of HOXA1 with immune cell infiltrations, immune checkpoints, HLAs, and chemotherapeutic sensitivity were evaluated. Colony formation, proliferation, and migration of LUAD cells with si-HOXA1 transfection were investigated, and the effects of HOXA1 on T cell exhaustion were assessed in vitro. Results. HOXA1 expression was a risk factor of overall survival, disease-specific survival, and progression-free interval of LUAD. HOXA1 exhibited prominent associations with immune cell infiltration, immune checkpoints, and HLAs. HOXA1-derived gene signature reliably and independently predicted LUAD outcomes. Also, high-risk cases presented increased sensitivity to cisplatin, paclitaxel, docetaxel, vinorelbine, and etoposide. HOXA1 knockdown exhibited an inhibitory effect on proliferation and migration abilities of LUAD cells. Silencing HOXA1 weakened the expression of antioxidative stress markers Nrf2/HO-1 and T cell exhaustion marker CD155 in LUAD cells. Moreover, LUAD cells with HOXA1 knockdown enhanced the CD8+ T cell response. Conclusion. Our data support the oncogenic function and prognostic significance of HOXA1 that facilitates immune escape and alleviates oxidative stress of LUAD.

HOXA1 is a radioresistance marker in multiple cancer types

“…We found that high HOXA1 expression was associated with poor prognosis and high recurrence risk in HNSCC and LGG patients who had undergone postoperative radiotherapy, and in NPC patients who had undergone radical radiotherapy, whereas HOXA1 had no predictive value with respect to prognosis in patients who underwent surgery alone. Many studies have reported that elevated HOXA1 expression is correlated with poor prognosis in multiple cancer types (30,31). However, little was known about whether high HOXA1 expression promotes the radioresistance of cancer cells.…”

Role of HOXA1-4 in the development of genetic and malignant diseases

“…Studies have demonstrated notable associations between HOXA1 and immune cell infiltration as well as immune checkpoints. Knockdown of HOXA1 in LUAD cells enhances the CD8 + T cell response [ 98 ].…”

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

“…Numerous studies have reported that HOX genes act as transcription factors, and these transcription products play key roles in the development of cancers 7 . HOXA family genes were identified as transcription factors that are involved in the development of various cancers, and have been reported to play important roles in TME 8,9 . Previous research has shown that HOXA7 is a member of the HOXA transcription factor family and was reported to play important roles in a number of malignancies including liver cancer, 10 colorectal cancer, 11 breast cancer, 12 and myeloid leukemia 13 .…”