Abstract | BACKGROUND: METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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Authors | Xizhen Xu, Guoping Wang, Yaqi Duan, Zitian Huo |
Journal | Pathology, research and practice
(Pathol Res Pract)
Vol. 229
Pg. 153693
(Jan 2022)
ISSN: 1618-0631 [Electronic] Germany |
PMID | 34826740
(Publication Type: Journal Article)
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Copyright | Copyright © 2021 Elsevier GmbH. All rights reserved. |
Chemical References |
- Biomarkers, Tumor
- Insm1 protein, mouse
- Repressor Proteins
- INSM1 protein, human
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Topics |
- Animals
- Biomarkers, Tumor
- Female
- Humans
- Lung Neoplasms
(etiology)
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Middle Aged
- Prognosis
- Repressor Proteins
(physiology)
- Small Cell Lung Carcinoma
(etiology)
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