Li Zhen-Hua, Liu Chang, Liu Qing-Hua, Wang Jian, Wang Ying, Wang Yan-Fei, Deng Shou-Jun, Li Ding-Biao
Department of Thoracic Surgery, Yan'an Affiliated Hospital of Kunming Medical University, Kunming, China.
J Thorac Dis. 2022 May;14(5):1466-1477. doi: 10.21037/jtd-22-29.
A hormonal role in the development of non-small cell lung cancer (NSCLC) has been well documented, and the classic estrogen receptors (ERs)-ERα and ERβ have been extensively investigated over the past decade. The expression of ERβ was found to be high and display biological activity in NSCLC, but anti-estrogen therapy targeting this receptor has shown limited efficacy for the disease. The third estrogen receptor, G protein-coupled estrogen receptor 1 (GPER1/GPR30), was recently found to be highly expressed in NSCLC. Herein, we aimed to investigate the expression profile of GPER1 and correlate it with clinicopathological factors as well as postoperative prognosis in NSCLC.
We examined GPER1 and ERβ expression using immunohistochemistry among 183 NSCLC cases, including 132 lung adenocarcinoma (LUAD) with identified epidermal growth factor receptor (EGFR) mutation status and 51 squamous cell carcinoma (SCC) patients. We then conducted correlation analysis between the expression of GPER1 and clinicopathological factors and patients' postoperative prognosis.
Positive expression of GPER1 was categorized into 2 main classes: nuclei-GPER1 (nGPER1) and concurrent nuclei-and cytoplasm-GPER1 (n/cGPER1), according to its subcellular localization. The LUAD with wild-type EGFR (wt-EGFR) had a higher frequency of n/cGPER1 (50%) but a lower frequency of nGPER1 (31%) when compared with those with mutated EGFR (n/cGPER1: 31%, nGPER1: 41%, respectively). The expression of GPER1, regardless of subcellular localization, was positively correlated with tumor stage and lymph node metastasis. The median recurrence-free survival (mRFS) and overall survival (OS) were significantly worse in participants with n/cGPER1 expression than in those with nGPER1 or without GPER1 expression.
This study revealed that GPER1 is aberrantly highly expressed and presents a unique GPER1 expression profile in NSCLC. The n/cGPER1 expression was significantly associated with EGFR mutation status, tumor stage, lymph node metastasis, and poor postoperative prognosis in NSCLC.
激素在非小细胞肺癌（NSCLC）发生发展中的作用已有充分记载，在过去十年中，经典雌激素受体（ERs）——ERα和ERβ已得到广泛研究。研究发现，ERβ在NSCLC中高表达并具有生物学活性，但针对该受体的抗雌激素治疗对该疾病的疗效有限。最近发现，第三种雌激素受体，即G蛋白偶联雌激素受体1（GPER1/GPR30）在NSCLC中高表达。在此，我们旨在研究GPER1的表达谱，并将其与NSCLC的临床病理因素及术后预后相关联。
我们采用免疫组织化学方法检测了183例NSCLC患者中GPER1和ERβ的表达，其中包括132例已确定表皮生长因子受体（EGFR）突变状态的肺腺癌（LUAD）患者和51例鳞状细胞癌（SCC）患者。然后，我们对GPER1的表达与临床病理因素及患者术后预后进行了相关性分析。
根据GPER1的亚细胞定位，其阳性表达主要分为两类：细胞核型GPER1（nGPER1）和细胞核与细胞质共表达型GPER1（n/cGPER1）。与EGFR突变型LUAD相比，野生型EGFR（wt-EGFR）的LUAD中n/cGPER1的频率较高（50%），但nGPER1的频率较低（31%）（n/cGPER1分别为31%，nGPER1分别为41%）。无论亚细胞定位如何，GPER1的表达均与肿瘤分期和淋巴结转移呈正相关。n/cGPER1表达的参与者的无复发生存期（mRFS）和总生存期（OS）的中位数明显差于nGPER1表达或无GPER1表达的参与者。
本研究表明，GPER1在NSCLC中异常高表达，并呈现出独特的GPER1表达谱。n/cGPER1表达与NSCLC中的EGFR突变状态、肿瘤分期、淋巴结转移及术后预后不良显著相关。
