Multi-Omics Analysis to Characterize Cigarette Smoke Induced Molecular Alterations in Esophageal Cells

Aafaque Ahmad Khan, Krishna Patel, Shankargouda Patil, Niraj Babu, Kiran K. Mangalaparthi, Hitendra Singh Solanki, Vishalakshi Nanjappa, Anjali Kumari, Malini Manoharan, Coral Karunakaran, Saktivel Murugan, Bipin Nair, Rekha V. Kumar, Manjusha Biswas, David Sidransky, Ravi Gupta, Rohit Gupta, Arati Khanna-Gupta, Prashant Kumar, Aditi ChatterjeeHarsha Gowda

Research output: Contribution to journalArticlepeer-review

Abstract

Though smoking remains one of the established risk factors of esophageal squamous cell carcinoma, there is limited data on molecular alterations associated with cigarette smoke exposure in esophageal cells. To investigate molecular alterations associated with chronic exposure to cigarette smoke, non-neoplastic human esophageal epithelial cells were treated with cigarette smoke condensate (CSC) for up to 8 months. Chronic treatment with CSC increased cell proliferation and invasive ability of non-neoplastic esophageal cells. Whole exome sequence analysis of CSC treated cells revealed several mutations and copy number variations. This included loss of high mobility group nucleosomal binding domain 2 (HMGN2) and a missense variant in mediator complex subunit 1 (MED1). Both these genes play an important role in DNA repair. Global proteomic and phosphoproteomic profiling of CSC treated cells lead to the identification of 38 differentially expressed and 171 differentially phosphorylated proteins. Bioinformatics analysis of differentially expressed proteins and phosphoproteins revealed that most of these proteins are associated with DNA damage response pathway. Proteomics data revealed decreased expression of HMGN2 and hypophosphorylation of MED1. Exogenous expression of HMGN2 and MED1 lead to decreased proliferative and invasive ability of smoke exposed cells. Immunohistochemical labeling of HMGN2 in primary ESCC tumor tissue sections (from smokers) showed no detectable expression while strong to moderate staining of HMGN2 was observed in normal esophageal tissues. Our data suggests that cigarette smoke perturbs expression of proteins associated with DNA damage response pathways which might play a vital role in development of ESCC.

Original languageEnglish (US)
Article number1666
JournalFrontiers in Oncology
Volume10
DOIs
StatePublished - Nov 5 2020

Keywords

  • DNA repair
  • cigarette smoke
  • esophageal squamous cell carcinoma
  • mass spectrometry
  • next generation sequencing
  • tandem mass tag

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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