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Cancer Gene Therapy (2022 )Cite this article

Mutations in ARID2 and TP53 genes are found to be implicated in the tobacco related tumorigeneses. However, the effect of loss of ARID2 in the TP53 mutated background in tobacco related cancer including oral cancer has not been investigated yet. Hence, in this study we knockdown ARID2 using shRNA mediated knockdown strategy in TP53 mutated oral squamous cell carcinoma (OSCC) cell line and studied its tumorigenic role. Our study revealed that suppression of ARID2 in TP53 mutated oral cancer cells increases cell motility and invasion, induces drastic morphological changes and leads to a marked increase in the expression levels of cytokeratins, and integrins, CK8, CK18 and β4-Integrin, markers of cell migration/invasion in oral cancer. ARID2 suppression also showed early onset and increased tumorigenicity in-vivo. Interestingly, transcriptome profiling revealed differentially expressed genes associated with migration and invasion in oral cancer cells including AKR1C2, NCAM2, NOS1, ADAM23 and genes of S100A family in ARID2 knockdown TP53 mutated oral cancer cells. Pathway analysis of differentially regulated genes identified “cancer pathways” and “PI3K/AKT Pathway” to be significantly dysregulated upon suppression of ARID2 in TP53 mutated OSCC cells. Notably, decreased ARID2 expression and increased CK8, CK18 expression leads to poor prognosis in Head and Neck cancer (HNSC) patients as revealed by Pan-Cancer TCGA data analysis. To conclude, our study is the first to demonstrate tumor suppressor role of ARID2 in TP53 mutated background indicating their cooperative role in OSCC, and also highlights its prognostic implications suggesting ARID2 as an important therapeutic target in OSCC.

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We would like to thank Genomics & NGS facility, electron microscopy facility, animal House, biorepository, ACTREC, Dr. Pradnya Kowtal and members of Sarin Lab. We are also grateful to TCGA/ULACAN databases to make data available free for analysis. We also thank NIBMG, and grant support from Department of Biotechnology, Govt. of India (Grant Number (BT/MB/01/ICGC/2009). We are grateful to Dr. T. Mahmoudi, Netherland for providing ARID2 antibody and Dr. Sorab Dalal, ACTREC, Mumbai for providing pLKO-PURO EGFP vector. The study has been supported by grant from Department of Biotechnology, Govt. of India (Grant Number (BT/MB/01/ICGC/2009) under the International Cancer Genome Consortium (ICGC) project.

These authors contributed equally: Pallavi Shukla, Prerana Dange.

Sarin Lab, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India

Pallavi Shukla, Prerana Dange & Rajiv Sarin

Comparative Oncology & Small Animal Imaging Facility, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India

Bhabani Shankar Mohanty & Pradip Chaudhari

Bioinformatics Centre, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India

Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India

Pradip Chaudhari & Rajiv Sarin

Cancer Genetics Clinic, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India

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PS conceptualized the idea, conducted cloning and molecular biology experiments, TCGA data analysis, designed and wrote the manuscript. PD performed cell culture and all functional assays and helped in animal experiments. PC supervised BSM in conducting all animal experiments. NG analyzed bioinformatics data. RS conceived the project, supervised all the experiments and edited the manuscript.

The authors declare no competing interests.

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Shukla, P., Dange, P., Mohanty, B.S. et al. ARID2 suppression promotes tumor progression and upregulates cytokeratin 8, 18 and β-4 integrin expression in TP53-mutated tobacco-related oral cancer and has prognostic implications. Cancer Gene Ther (2022). https://doi.org/10.1038/s41417-022-00505-x

DOI: https://doi.org/10.1038/s41417-022-00505-x

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Cancer Gene Therapy (Cancer Gene Ther) ISSN 1476-5500 (online) ISSN 0929-1903 (print)