Li Nan, Liu Kaisheng, Dong Shaowei, Ou Ling, Li Jieling, Lai Minshan, Wang Yue, Bao Yucheng, Shi Huijie, Wang Xiao, Wang Shaoxiang
School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen, China.
Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.
Front Oncol. 2020 Nov 16;10:571167. doi: 10.3389/fonc.2020.571167. eCollection 2020.
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumors and there is a lack of biomarkers for ESCC diagnosis and prognosis. Family subunits of cholinergic nicotinic receptor genes (CHRNs) are involved in smoking behavior and tumor cell proliferation. Previous researches have shown similar molecular features and pathogenic mechanisms among ESCC, head and neck squamous cell carcinoma (HNSC), and lung squamous cell carcinoma (LUSC). Using edgeR, three mutual differentially expressed genes of CHRNs were found to be significantly upregulated at the mRNA level in ESCC, LUSC, and HNSC compared to matched normal tissues. Kaplan-Meier survival analysis showed that high expression of CHRNB4 was associated with unfavorable prognosis in ESCC and HNSC. The specific expression analysis revealed that CHRNB4 is highly expressed selectively in squamous cell carcinomas compared to adenocarcinoma. Cox proportional hazards regression analysis was performed to find that just the single gene CHRNB4 has enough independent prognostic ability, with the area under curve surpassing the tumor-node-metastasis (TNM) staging-based model, the most commonly used model in clinical application in ESCC. In addition, an effective prognostic nomogram was established combining the TNM stage, gender of patients, and expression of CHRNB4 for ESCC patients, revealing an excellent prognostic ability when compared to the model of CHRNB4 alone or TNM. Gene Set Enrichment Analysis results suggested that the expression of CHRNB4 was associated with cancer-related pathways, such as the mTOR pathway. Cell Counting Kit-8, cloning formation assay, and western blot proved that CHRNB4 knockdown can inhibit the proliferation of ESCC cells the Akt/mTOR and ERK1/2/mTOR pathways, which might facilitate the prolonged survival of patients. Furthermore, we conducted structure-based molecular docking, and potential modulators against CHRNB4 were screened from FDA approved drugs. These findings suggested that CHRNB4 specifically expressed in SCCs, and may serve as a promising biomarker for diagnosis and prognosis prediction, and it can even become a therapeutic target of ESCC patients.
食管鳞状细胞癌（ESCC）是最具侵袭性的恶性肿瘤之一，目前缺乏用于ESCC诊断和预后评估的生物标志物。胆碱能烟碱受体基因（CHRNs）家族亚基参与吸烟行为和肿瘤细胞增殖。先前的研究表明，ESCC、头颈部鳞状细胞癌（HNSC）和肺鳞状细胞癌（LUSC）具有相似的分子特征和致病机制。使用edgeR软件，发现与匹配的正常组织相比，CHRNs的三个共同差异表达基因在ESCC、LUSC和HNSC的mRNA水平上显著上调。Kaplan-Meier生存分析表明，CHRNB4的高表达与ESCC和HNSC的不良预后相关。特异性表达分析显示，与腺癌相比，CHRNB4在鳞状细胞癌中选择性高表达。进行Cox比例风险回归分析发现，仅单个基因CHRNB4就具有足够的独立预后能力，其曲线下面积超过了基于肿瘤-淋巴结-转移（TNM）分期的模型，这是ESCC临床应用中最常用的模型。此外，结合TNM分期、患者性别和CHRNB4表达，为ESCC患者建立了有效的预后列线图，与单独的CHRNB4模型或TNM模型相比，显示出优异的预后能力。基因集富集分析结果表明，CHRNB4的表达与癌症相关通路有关，如mTOR通路。细胞计数试剂盒-8、克隆形成试验和蛋白质免疫印迹证明，敲低CHRNB4可抑制ESCC细胞的增殖，以及Akt/mTOR和ERK1/2/mTOR通路，这可能有助于延长患者的生存期。此外，我们进行了基于结构的分子对接，并从FDA批准的药物中筛选出了针对CHRNB4的潜在调节剂。这些发现表明，CHRNB4在鳞状细胞癌中特异性表达，可能作为一种有前景的生物标志物用于诊断和预后预测，甚至可能成为ESCC患者的治疗靶点。
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