Loss of expression and prognosis value of alpha-internexin in gastroenteropancreatic neuroendocrine neoplasm

BMC Cancer. 2018 Jun 26;18(1):691. doi: 10.1186/s12885-018-4449-8.


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 (χ2 = 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.

Keywords: Gastroenteropancreatic neuroendocrine neoplasm. Alpha-internexin. Expression. Prognosis.

MeSH terms

  • Adult
  • Aged
  • CpG Islands
  • DNA Methylation
  • Female
  • Humans
  • Immunohistochemistry
  • Intermediate Filament Proteins / analysis
  • Intermediate Filament Proteins / genetics
  • Intermediate Filament Proteins / physiology*
  • Intestinal Neoplasms / chemistry
  • Intestinal Neoplasms / mortality*
  • Intestinal Neoplasms / pathology
  • Male
  • Middle Aged
  • Neuroendocrine Tumors / chemistry
  • Neuroendocrine Tumors / mortality*
  • Neuroendocrine Tumors / pathology
  • Pancreatic Neoplasms / chemistry
  • Pancreatic Neoplasms / mortality*
  • Pancreatic Neoplasms / pathology
  • Prognosis
  • Stomach Neoplasms / chemistry
  • Stomach Neoplasms / mortality*
  • Stomach Neoplasms / pathology


  • Intermediate Filament Proteins
  • alpha-internexin

Supplementary concepts

  • Gastro-enteropancreatic neuroendocrine tumor