Genome-wide transcriptional analysis of Aristolochia manshuriensis induced gastric carcinoma

Pharm Biol. 2020 Dec;58(1):98-106. doi: 10.1080/13880209.2019.1710219.

Abstract

Context: Aristolochia manshuriensis Kom (Aristolochiaceae) (AMK) is known for toxicity and mutagenicity.Objective: The tumorigenic role of AMK has yet to be understood.Materials and methods: AMK extracts were extracted from root crude drug. SD (Sprague Dawley) rats underwent gavage with AMK (0.92 g/kg) every other day for 10 (AMK-10) or 20 (AMK-20) weeks. Stomach samples were gathered for histopathological evaluation, microarray and mRNA analysis.Results: The gastric weight to body weight ratio (GW/BW) is 1.7 in the AMK-10 cohort, and 1.8 in AMK-20 cohort compared to control (CTL) cohort. Liver function was damaged in AMK-10 and AMK-20 rats compared to CTL rats. There were no significant changes of CRE (creatinine) in AMK-10 and AMK-20 rats. Histopathological analysis revealed that rats developed dysplasia in the forestomach in AMK-10 rats, and became gastric carcinoma in AMK-20 rats. Genes including Mapk13, Nme1, Gsta4, Gstm1, Jun, Mgst2, Ggt6, Gpx2, Gpx8, Calml3, Rasgrp2, Cd44, Gsr, Dgkb, Rras, and Amt were found to be critical in AMK-10 and AMK-20 rats. Pik3cb, Plcb3, Tp53, Hras, Myc, Src, Akt1, Gnai3, and Fgfr3 worked in AMK-10 rats, and PDE2a and PDE3a played a pivotal role in AMK-20 rats.Discussion and conclusions: AMK induced benign or malignant gastric tumours depends on the period of AMK administration. Genes including Mapk13, Nme1, Gsta4, Gstm1, Jun, Mgst2, Ggt6, Gpx2, Gpx8, Calml3, Rasgrp2, Cd44, Gsr, Dgkb, Rras, Amt, Pik3cb, Plcb3, Tp53, Hras, Myc, Src, Akt1, Gnai3, Fgfr3, PDE2a, and PDE3a were found to be critical in aristolochic acid-induced gastric tumour process.

Keywords: Gastric tumour; aristolochic acids; benign tumour; malignant tumour.

MeSH terms

  • Animals
  • Aristolochia / chemistry*
  • Aristolochic Acids / isolation & purification
  • Aristolochic Acids / toxicity
  • Microarray Analysis
  • Plant Extracts / administration & dosage
  • Plant Extracts / toxicity*
  • Rats
  • Rats, Sprague-Dawley
  • Stomach Neoplasms / chemically induced*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / pathology
  • Time Factors

Substances

  • Aristolochic Acids
  • Plant Extracts
  • aristolochic acid I

Grants and funding

This work was supported by the National Science and Technology Major Project (2015ZX09501004, 2018ZX09101002-003), Beijing Science and Technology Projects (Z151100000115012 and Z161100004916025), China Academy of Chinese Medical Sciences Foundation (ZZ10-025 and ZZ12-001) and National Natural Science Foundation of China (81703808).