Molecular Characterization of Esophageal Squamous Cell Carcinoma Using Quantitative Proteomics

Kiran K Mangalaparthi; Krishna Patel; Aafaque Ahmad Khan; Bipin Nair; Rekha V Kumar; Thottethodi Subrahmanya Keshav Prasad; David Sidransky; Aditi Chatterjee; Akhilesh Pandey; Harsha Gowda

doi:10.3390/cancers15133302

Molecular Characterization of Esophageal Squamous Cell Carcinoma Using Quantitative Proteomics

Cancers (Basel). 2023 Jun 23;15(13):3302. doi: 10.3390/cancers15133302.

Authors

Kiran K Mangalaparthi^{1

2

3}, Krishna Patel^{1

2}, Aafaque Ahmad Khan¹, Bipin Nair², Rekha V Kumar⁴, Thottethodi Subrahmanya Keshav Prasad^{1

2

5}, David Sidransky^{6

7}, Aditi Chatterjee^{1

2

8}, Akhilesh Pandey^{1

3

8

9

10}, Harsha Gowda^{1

2

8}

Affiliations

¹ Institute of Bioinformatics, International Technology Park, Bangalore 560066, India.
² Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam 691001, India.
³ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
⁴ Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore 560066, India.
⁵ Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore 575018, India.
⁶ Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁷ Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ Manipal Academy of Higher Education, Manipal 576104, India.
⁹ Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
¹⁰ Center for Molecular Medicine, National Institute of Mental Health and Neurosciences, Hosur Road, Bangalore 560029, India.

Abstract

Esophageal squamous cell carcinoma (ESCC) is a heterogeneous cancer associated with a poor prognosis in advanced stages. In India, it is the sixth most common cause of cancer-related mortality. In this study, we employed high-resolution mass spectrometry-based quantitative proteomics to characterize the differential protein expression pattern associated with ESCC. We identified several differentially expressed proteins including PDPN, TOP2A, POSTN and MMP2 that were overexpressed in ESCC. In addition, we identified downregulation of esophagus tissue-enriched proteins such as SLURP1, PADI1, CSTA, small proline-rich proteins such as SPRR3, SPRR2A, SPRR1A, KRT4, and KRT13, involved in squamous cell differentiation. We identified several overexpressed proteins mapped to the 3q24-29 chromosomal region, aligning with CNV alterations in this region reported in several published studies. Among these, we identified overexpression of SOX2, TP63, IGF2BP2 and RNF13 that are encoded by genes in the 3q26 region. Functional enrichment analysis revealed proteins involved in cell cycle pathways, DNA replication, spliceosome, and DNA repair pathways. We identified the overexpression of multiple proteins that play a major role in alleviating ER stress, including SYVN1 and SEL1L. The SYVN1/SEL1L complex is an essential part of the ER quality control machinery clearing misfolded proteins from the ER. SYVN1 is an E3 ubiquitin ligase that ubiquitinates ER-resident proteins. Interestingly, there are also other non-canonical substrates of SYVN1 which are known to play a crucial role in tumor progression. Thus, SYVN1 could be a potential therapeutic target in ESCC.

Keywords: ER stress; SYVN1; cell cycle regulation; endoplasmic reticulum-associated degradation (ERAD); esophageal squamous cell carcinoma; quantitative proteomics.

Grants and funding

We thank the Department of Biotechnology (DBT), Government of India for research support to the Institute of Bioinformatics (IOB), Bangalore. IOB was supported by DBT Program Support on Neuroproteomics and infrastructure for proteomic data analysis (BT/01/COE/08/05). K.K.M. is a recipient of a Junior Research Fellowship from the University Grants Commission (UGC). K.P. is the recipient of a Senior Research Fellowship from the Council of Scientific and Industrial Research (CSIR).