Loss of Expression and Prognosis Value of Alpha-internexin in Gastroenteropancreatic Neuroendocrine Neoplasm

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2018 Jun 27

PMID 29940892

Citations 4

Authors

Yuhong Wang

Yuanjia Chen

Xiaoxing Li

Wanming Hu

Yu Zhang

Luohai Chen

Minhu Chen

Jie Chen

Affiliations

Soon will be listed here.

Abstract

Background: The neuronal intermediate filament alpha-internexin (α-internexin) is a cytoskeleton protein which is involved in the tumor initiation and progression. In this study, we examined the expression and prognosis value of α-internexin in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs).

Methods: α-internexin was detected with immunohistochemical staining in 286 tumor specimens from patients with GEP-NENs. Methylation status of α-internexin was evaluated by bisulfite genomic sequencing. We assessed the prognostic value of α-internexin and its correlation with relevant clinicalpathological characteristics.

Results: The reduced/loss of expression rate of α-internexin in GEP-NEN was 73.4% (210/286), while the positive expression rate was 26.6% (76/286). The difference of α-internexin deficiency was not statistically significant between gastrointestinal NENs (GI-NENs) and pancreatic NENs (pNENs). However, we found significant difference of reduced/loss of α-internexin expression among different sites of GI-NENs (χ = 43.470, P < 0.001). The reduced/loss of expression of α-internexin was significantly associated with poorly differentiation (P < 0.001) and advanced tumor stage (P < 0.001). Univariate analyses showed that reduced/loss of expression of α-internexin predicted worse overall survival (OS) in GEP-NEN patients (P < 0.001), especially in subtype of GI-NENs (P < 0.001). However, in multivariable regression analysis, α-internexin expression was not an independent prognostic factor. The hypermethylation of α-internexin gene was significantly correlated with protein deficiency in GI-NENs, but not in pNENs. Hypermethylation of several CpG sites was significantly associated with poorly differentiated and advanced stage (P values range from 0.018 to 0.044). However, the methylation status of α-internexin was not associated with patient OS.

Conclusions: The expression of α-internexin was highly heterougeneous in different sites of GEP-NENs. The reduced/loss of expression of α-internexin was closely related to tumors with aggressiveness and patient's adverse prognosis. The hypermethylation of the regulatory region examined may be an important epigenetic regulation mechanism of α-internexin deficiency in subtype of GI-NENs.

Citing Articles

DNA Methylation in , , and Is Associated with Metastatic Disease in Renal Cell Carcinoma.

Katzendorn O, Peters I, Dubrowinskaja N, Moog J, Reese C, Tezval H Cancers (Basel). 2022; 14(1).

PMID: 35008203 PMC: 8750163. DOI: 10.3390/cancers14010039.

Development and Validation of a Radiosensitivity Prediction Model for Lower Grade Glioma Based on Spike-and-Slab Lasso.

Du Z, Cai S, Yan D, Li H, Zhang X, Yang W Front Oncol. 2021; 11:701500.

PMID: 34395274 PMC: 8363254. DOI: 10.3389/fonc.2021.701500.

Multi-Omics Data Integration Analysis of an Immune-Related Gene Signature in LGG Patients With Epilepsy.

Cheng Q, Duan W, He S, Li C, Cao H, Liu K Front Cell Dev Biol. 2021; 9:686909.

PMID: 34336837 PMC: 8322853. DOI: 10.3389/fcell.2021.686909.

Prognostic and predictive factors on overall survival and surgical outcomes in pancreatic neuroendocrine tumors: recent advances and controversies.

Lee L, Ito T, Jensen R Expert Rev Anticancer Ther. 2019; 19(12):1029-1050.

PMID: 31738624 PMC: 6923565. DOI: 10.1080/14737140.2019.1693893.

References

Rindi G, Kloppel G, Alhman H, Caplin M, Couvelard A, de Herder W . TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2006; 449(4):395-401. PMC: 1888719. DOI: 10.1007/s00428-006-0250-1. View

Zhao J, Liem R . α-Internexin and Peripherin: Expression, Assembly, Functions, and Roles in Disease. Methods Enzymol. 2016; 568:477-507. DOI: 10.1016/bs.mie.2015.09.012. View

Liu B, Tang L, Liu Z, Mei M, Yu R, Dhall D . α-Internexin: a novel biomarker for pancreatic neuroendocrine tumor aggressiveness. J Clin Endocrinol Metab. 2014; 99(5):E786-95. DOI: 10.1210/jc.2013-2874. View

Ushijima T . Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer. 2005; 5(3):223-31. DOI: 10.1038/nrc1571. View

Foley J, Witte D, Chiu F, Parysek L . Expression of the neural intermediate filament proteins peripherin and neurofilament-66/alpha-internexin in neuroblastoma. Lab Invest. 1994; 71(2):193-9. View

Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, Diaz-Perez J, Martinez Del Prado M, Alonso Orduna V . Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Ann Oncol. 2010; 21(9):1794-1803. DOI: 10.1093/annonc/mdq022. View

Yao J, Hassan M, Phan A, Dagohoy C, Leary C, Mares J . One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008; 26(18):3063-72. DOI: 10.1200/JCO.2007.15.4377. View

Mokhtari K, Ducray F, Kros J, Gorlia T, Idbaih A, Taphoorn M . Alpha-internexin expression predicts outcome in anaplastic oligodendroglial tumors and may positively impact the efficacy of chemotherapy: European organization for research and treatment of cancer trial 26951. Cancer. 2011; 117(13):3014-26. DOI: 10.1002/cncr.25827. View

Esteller M . Epigenetics in cancer. N Engl J Med. 2008; 358(11):1148-59. DOI: 10.1056/NEJMra072067. View

10.

Park Y, Claus R, Weichenhan D, Plass C . Genome-wide epigenetic modifications in cancer. Prog Drug Res. 2010; 67:25-49. PMC: 3066002. DOI: 10.1007/978-3-7643-8989-5_2. View

11.

Schultz M, He Y, Whitaker J, Hariharan M, Mukamel E, Leung D . Human body epigenome maps reveal noncanonical DNA methylation variation. Nature. 2015; 523(7559):212-6. PMC: 4499021. DOI: 10.1038/nature14465. View

12.

Ducray F, Mokhtari K, Criniere E, Idbaih A, Marie Y, Dehais C . Diagnostic and prognostic value of alpha internexin expression in a series of 409 gliomas. Eur J Cancer. 2011; 47(5):802-8. DOI: 10.1016/j.ejca.2010.11.031. View

13.

Schimmack S, Lawrence B, Svejda B, Alaimo D, Schmitz-Winnenthal H, Fischer L . The clinical implications and biologic relevance of neurofilament expression in gastroenteropancreatic neuroendocrine neoplasms. Cancer. 2011; 118(10):2763-75. PMC: 3312048. DOI: 10.1002/cncr.26592. View

14.

Ishida M, Kushima R, Brevet M, Chatelain D, Okabe H . Co-expression of neuronal intermediate filaments, peripherin and α-internexin in human well-differentiated endocrine neoplasms (carcinoid tumors) of the appendix. Mol Med Rep. 2011; 1(2):191-5. View

15.

Rindi G, Kloppel G, Couvelard A, Komminoth P, Korner M, Lopes J . TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2007; 451(4):757-62. DOI: 10.1007/s00428-007-0452-1. View

16.

Weber M, Hellmann I, Stadler M, Ramos L, Paabo S, Rebhan M . Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet. 2007; 39(4):457-66. DOI: 10.1038/ng1990. View

17.

Taby R, Issa J . Cancer epigenetics. CA Cancer J Clin. 2010; 60(6):376-92. DOI: 10.3322/caac.20085. View

18.

Kaya B, Mena H, Miettinen M, Rushing E . Alpha-internexin expression in medulloblastomas and atypical teratoid-rhabdoid tumors. Clin Neuropathol. 2003; 22(5):215-21. View

19.

Modlin I, Oberg K, Chung D, Jensen R, de Herder W, Thakker R . Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2008; 9(1):61-72. DOI: 10.1016/S1470-2045(07)70410-2. View