Xu Xizhen, Wang Guoping, Duan Yaqi, Huo Zitian
Institute of Pathology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, PR China; Department of Pathology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
Institute of Pathology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, PR China; Department of Pathology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
Pathol Res Pract. 2022 Jan;229:153693. doi: 10.1016/j.prp.2021.153693. Epub 2021 Nov 22.
Small cell lung cancer (SCLC) is a malignant lung neuroendocrine tumor with early metastasis, rapid progression, and poor outcomes. Insulinoma-associated protein 1 (INSM1) has been an excellent marker for neuroendocrine (NE) differentiation and widely used in the diagnosis of NE neoplasms, including SCLC. However, its role beyond NE diagnostic marker remained little reported.
We examined immunohistochemical expression of INSM1 in 73 surgically resected SCLC, analyzed its prognostic value by Kaplan-Meier method, and investigated clinical-pathological features of INSM1 high SCLC. In vitro, We assessed INSM1 function on glucose intake, tumor migration, and Cisplatin resistance by 2-NBDG glucose uptake fluorescent assay, transwell assay, and ANNEXIN V/PI assay, respectively. In vivo, we evaluated the therapeutic value of metformin on reversing INSM1 induced chemoresistance by BALB/c nude mice xenograft tumor model.
High INSM1 expression was correlated with lymph node metastasis (LNM) (p = 0.0005), later TNM stages (p = 0.0003), and predicted poor survival (Log-rank p = 0.038). Multivariate Cox analysis confirmed INSM1 as an independent prognostic factor in SCLC (p = 0.012, HR:3.195, 95%CI:1.288-7.927). Interestingly, LNM was correlated with worse prognosis only in patients received chemotherapy (Log-rank p = 0.027) rather than the others (Log-rank p = 0.40). In patients having LNM and treated with chemotherapy, high INSM1 was correlated with worse clinic outcome (Log-rank p = 0.009). In vitro, overexpression of INSM1 decreased AMPK-α expression as well as glucose intake, promoted tumor cell migration, and limited the apoptosis induced by Cisplatin, which all could be reversed by Metformin. In vivo, INSM1 overexpression also contributed to tumor growth beyond inducing Cisplatin resistance.
Our finding suggested INSM1 played more role than a NE marker, partly through down-regulating AMPK signal. INSM1 may serve as a novel prognostic marker and therapeutic target in SCLC.
小细胞肺癌（SCLC）是一种恶性肺神经内分泌肿瘤，具有早期转移、进展迅速和预后不良的特点。胰岛素瘤相关蛋白1（INSM1）一直是神经内分泌（NE）分化的优良标志物，广泛应用于包括SCLC在内的NE肿瘤的诊断。然而，其在NE诊断标志物之外的作用报道较少。
我们检测了73例手术切除的SCLC中INSM1的免疫组化表达，采用Kaplan-Meier法分析其预后价值，并研究INSM1高表达SCLC的临床病理特征。在体外，我们分别通过2-NBDG葡萄糖摄取荧光测定法、Transwell测定法和膜联蛋白V/碘化丙啶测定法评估INSM1对葡萄糖摄取、肿瘤迁移和顺铂耐药性的作用。在体内，我们通过BALB/c裸鼠异种移植瘤模型评估二甲双胍对逆转INSM1诱导的化疗耐药性的治疗价值。
INSM1高表达与淋巴结转移（LNM）相关（p = 0.0005），与较晚的TNM分期相关（p = 0.0003），并预示生存不良（对数秩检验p = 0.038）。多因素Cox分析证实INSM1是SCLC的独立预后因素（p = 0.012，HR：3.195，95%CI：1.288-7.927）。有趣的是，LNM仅在接受化疗的患者中与较差的预后相关（对数秩检验p = 0.027），而在其他患者中则不然（对数秩检验p = 0.40）。在有LNM且接受化疗的患者中，INSM1高表达与较差的临床结局相关（对数秩检验p = 0.009）。在体外，INSM1的过表达降低了AMPK-α的表达以及葡萄糖摄取，促进了肿瘤细胞迁移，并限制了顺铂诱导的细胞凋亡，而这些作用均可被二甲双胍逆转。在体内，INSM1的过表达除了诱导顺铂耐药外，还促进了肿瘤生长。
我们的研究结果表明，INSM1的作用不止是一个NE标志物，部分是通过下调AMPK信号发挥作用。INSM1可能是SCLC的一种新型预后标志物和治疗靶点。
