Downregulation of HOXA13 sensitizes human esophageal squamous cell carcinoma to chemotherapy

Abstract

BackgroundChemoresistance often develops in esophageal squamous cell carcinoma (ESCC), leading to poor prognosis. HOX genes play a crucial role in embryonic development and cell differentiation. Studies have recently linked HOX with chemoresistance, thus we explored whether HOXA13 is involved in ESCC chemoresistance.MethodsOne hundred thirty‐one ESCC patients who received neoadjuvant chemotherapy were enrolled. HOXA13 expression was examined by immunohistochemistry. RNA interference was used to knock down the HOXA13 expression in KYSE70 and transfected HOXA13 plasmid to overexpress HOXA13 in KYSE510 cells. We examined half‐maximal inhibitory concentration of cisplatin, apoptosis, and epithelial‐to‐mesenchymal transition (EMT) in ESCC cell lines with different HOXA13 expression levels by cell counting kit‐8, flow cytometry, and transwell analysis.ResultsThe median survival of patients with high HOXA13 expression was significantly shorter than those with low expression (P = 0.027). HOXA13 was associated with worse tumor regression grade (P = 0.009). Low HOXA13 expressed cells decreased the half‐maximal inhibitory concentration of cisplatin (P < 0.05), increased cisplatin‐induced apoptosis (P < 0.05), and decreased EMT (P < 0.05) compared with high HOXA13 expressed cells. In low HOXA13 expressed cells, cleaved caspase‐3 and cleaved PARP expression induced by cisplatin increased, while expression of E‐cadherin and Snail protein, markers of EMT, was upregulated and downregulated, respectively. EMT decreased in low HOXA13 expressed cells.ConclusionHigh HOXA13 expression was associated with inferior tumor regression grade and poor overall survival in ESCC patients treated with neoadjuvant chemotherapy. HOXA13 increased cisplatin‐resistance and promoted EMT in ESCC cells.

Paralogous HOX13 Genes in Human Cancers

“…The coordinated expression of HOXA13, ANXA2 and SOD2 strongly predicts poor prognosis in ESCC [47]. HOXA13 is also involved in the modulation of EMT in ESCC cells [48]. In ESCC patients treated with neoadjuvant chemotherapy, HOXA13 expression is associated with the worst tumor regression grade.…”

“…In ESCC patients treated with neoadjuvant chemotherapy, HOXA13 expression is associated with the worst tumor regression grade. The knockdown of HOXA13, in ESCC cells, increases cis-platinum-induced apoptosis, suggesting an essential role of HOXA13 in drug-resistance acquisition [48]. In a further investigation, an opposite trend of HOXA13 expression has been detected in oral squamous cell carcinoma (OSCC): a prevalent HOXA13 expression, in the superficial side of the lesions, is significantly associated to a better prognosis of OSCC patients [27].…”

Expression Profile and Prognostic Values of HOXA Family Members in Laryngeal Squamous Cell Cancer

“…HOXA13 knockdown significantly restored the epithelial characteristics and reduced the mesenchymal characteristics of the cancer cells via the transforming growth factor (TGF)-β signaling pathway (35). Moreover, HOXA13 expression negatively affects cisplatin sensitivity in human esophageal squamous cells and overall survival in patients with esophageal squamous cell carcinoma (38). Our results showed that multiple cancer-associated pathways were identified in LSCC tissues with high expression of HOXA13, and high expression of HOXA13 in LSCC predicted poor overall survival.…”

Targeting CDC7 improves sensitivity to chemotherapy of esophageal squamous cell carcinoma

“…Accumulating evidence have indicated that multiple molecules were involved in anticancer drug resistance of ESCC 9,26–31. For example, IL6 was found to promote chemoresistance in ESCC via CXCR7,26 and downregulation of HOXA13 sensitizes human ESCC to chemotherapy and might regulate epithelial-to-mesenchymal transition (EMT) 30. CDC7 has been reported to promote tumor chemoresistance and survival via multiple pathways 20.…”