Chen Dong, Zhang Min, Ruan Jian, Li Xiaolin, Wang Saisai, Cheng Xiaofei, Zhao Huiying, Zeng Ying, Liu Jingjing, He Kangxin, Zhao Peng
Department of Colorectal Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China.
College of Medicine, Zhejiang University, Hangzhou 310058, Zhejiang Province, China.
J Cancer. 2020 Aug 18;11(20):6050-6058. doi: 10.7150/jca.49809. eCollection 2020.
Metastasis is the primary cause of death in colorectal cancer (CRC); the underlying mechanisms remain partly unknown. In this study, we aim to investigate the value of HOXA11-AS in survival evaluation and the potential role of HOXA11-AS/miR-149-3p axis in the CRC metastasis. The expressions of HOXA11-AS, both in obtained CRC samples and adjacent noncancerous tissues, were analyzed in survival evaluation. Competing endogenous RNAs (CeRNAs) Analysis were employed to reveal the potential relationship between HOXA11-AS and miR-149-3p. It was further confirmed by Quantitative real-time polymerase chain reaction (qRT-PCR) and Dual-luciferase reporter assay. Migration and invasion assay were used to verify the potential role of HOXA11-AS and miR-149-3p in the regulation of CRC metastasis. The potential pathway was explored by Western blot analysis. The expression of HOXA11-AS in the CRC tissue is significantly higher than the expression in adjacent noncancerous tissue (p<0.0001). High expressions of HOXA11-AS were noticeably correlated with clinicopathologic characteristics including advanced clinical stage (p=0.021), larger tumor size (p<0.001) and frequent tumor recurrence (p=0.001). The overall survival in HOXA11-AS-High group was significantly shorter than the HOXA11-AS-Low group (p<0.001). Advanced clinical stage, tumor size and high expression of HOXA11-AS were showed as independent prognostic prediction factors for the 5-year tumor relapse of CRC patients (p<0.001). HOXA11-AS acts as a potential molecular sponge for miR-149-3p, in the promotion of CRC metastasis. In the miR-149-3p mimic-treated group, the expression of E-cadherin was increased, whereas the expression of N-cadherin, Snail, Slug, TGF-β1, Wnt2b, Twist and C/EBPβ was decreased. This study demonstrates that high expression of HOXA11-AS is correlated with CRC progression and poor prognosis and may promote metastasis via EMT by modulating miR-149-3p.
转移是结直肠癌（CRC）患者死亡的主要原因，其潜在机制仍部分未知。在本研究中，我们旨在探讨HOXA11-AS在生存评估中的价值以及HOXA11-AS/miR-149-3p轴在CRC转移中的潜在作用。在生存评估中分析了HOXA11-AS在获取的CRC样本和相邻非癌组织中的表达。采用竞争性内源RNA（CeRNA）分析来揭示HOXA11-AS与miR-149-3p之间的潜在关系。通过定量实时聚合酶链反应（qRT-PCR）和双荧光素酶报告基因检测进一步证实。采用迁移和侵袭实验来验证HOXA11-AS和miR-149-3p在调节CRC转移中的潜在作用。通过蛋白质免疫印迹分析探索潜在途径。HOXA11-AS在CRC组织中的表达显著高于相邻非癌组织（p<0.0001）。HOXA11-AS的高表达与包括临床晚期（p=0.021）、肿瘤体积较大（p<0.001）和肿瘤频繁复发（p=0.001）等临床病理特征显著相关。HOXA11-AS高表达组的总生存期显著短于HOXA11-AS低表达组（p<0.001）。临床晚期、肿瘤大小和HOXA11-AS的高表达被证明是CRC患者5年肿瘤复发的独立预后预测因素（p<0.001）。HOXA11-AS作为miR-149-3p的潜在分子海绵，促进CRC转移。在miR-149-3p模拟物处理组中，E-钙黏蛋白的表达增加，而N-钙黏蛋白、Snail、Slug、TGF-β1、Wnt2b、Twist和C/EBPβ的表达降低。本研究表明，HOXA11-AS的高表达与CRC进展和不良预后相关，可能通过调节miR-149-3p经由上皮-间质转化促进转移。
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