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Differentially expressed full-length, fusion and novel isoforms transcripts-based signature of well-differentiated keratinized oral squamous cell carcinoma

Neetu Singh _, Dinesh Kumar Sahu, Ratnesh Kumar Tripathi, Archana Mishra, Hari Shyam, Pratap Shankar, Mayank Jain, Nawazish Alam, Anil Kumar, Abhishek Mishra, Rebecca Chowdhry, Anjana Singh, Sameer Gupta, Divya Mehrotra, Preeti Agarwal, Madhu Mati Goel, Arun Chaturvedi, Satya Prakash Agarwal, Manish Bajpai, Devendra Kumar Gupta, Madan Lal Brahma Bhatt and Ravi Kant

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Oncotarget. 2020; 11:3227-3243. https://doi.org/10.18632/oncotarget.27693

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Abstract

Neetu Singh1,*, Dinesh Kumar Sahu1,*, Ratnesh Kumar Tripathi1,*, Archana Mishra1,2, Hari Shyam1, Pratap Shankar1, Mayank Jain1, Nawazish Alam1, Anil Kumar1, Abhishek Mishra1, Rebecca Chowdhry3, Anjana Singh4, Sameer Gupta5, Divya Mehrotra6, Preeti Agarwal7, Madhu Mati Goel7, Arun Chaturvedi5, Satya Prakash Agarwal8, Manish Bajpai9, Devendra Kumar Gupta10, Madan Lal Brahma Bhatt11 and Ravi Kant12

1 Department of Molecular Biology, Center for Advance Research, King George's Medical University, Lucknow, India

2 Department of Surgery, King George’s Medical University, Lucknow, India

3 Department of Periodontology, All India Institute of Medical Sciences, Rishikesh, India

4 Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, India

5 Department of Surgical Oncology, King George's Medical University, Lucknow, India

6 Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow, India

7 Department of Pathology, King George's Medical University, Lucknow, India

8 Department of Otorhinolaryngology, King George's Medical University, Lucknow, India

9 Department of Physiology, King George's Medical University, Lucknow, India

10 Department of Pediatric Surgery, Super Speciality Pediatric Hospital and Post Graduate Teaching Institute, Noida, India

11 Department of Radiotherapy, King George's Medical University, Lucknow, India

12 Department of Surgical Oncology, All India Institute of Medical Sciences, Rishikesh, India

* These authors contributed equally to this work

Correspondence to:

Neetu Singh,email: neetusingh@kgmcindia.edu

Keywords: oral tongue squamous cell carcinoma; microarray; transcriptomics; integrative bioinformatics; differentially expressed gene

Received: May 11, 2020     Accepted: July 14, 2020     Published: August 25, 2020

ABSTRACT

Highly keratinized oral squamous cell carcinoma (OSCC) exhibits an improved response to treatment and prognosis compared with weakly keratinized OSCC. Therefore, we aimed to develop gene transcript signature and to identify novel full-length isoforms, fusion transcript and non-coding RNA to differentiate well-differentiated (WD) with Moderately Differentiated (MD)/Poorly Differentiated (PD)/WD-lymphadenopathy OSCC through, HTA, Isoform sequencing, and NanoString. Additionally, specific copy number gain and loss were also identify in WD keratinized OSCC through Oncoscan array and validated through Real-time PCR in histopathologically characterized FFPE-WD keratinized OSCC. Three-hundred-thirty-eight (338) differentially expressed full-length (FL) transcript isoforms (317 upregulated and 21 down-regulated in OSCC) were identified through Isoform Sequencing using the PacBio platform. Thirty-four (34) highly upregulated differentially expressed transcripts from IsoSeq data were also correlated with HTA2.0 and validated in 42 OSCC samples. We were able to identify 18 differentially expressed transcripts, 12 fusion transcripts, and two long noncoding RNAs. These transcripts were involved in increased cell proliferation, dysregulated metabolic reprogramming, oxidative stress, and immune system markers with enhanced immune rearrangements, suggesting a cancerous nature. However, an increase in proteasomal activity and hemidesmosome proteins suggested an improved prognosis and tumor cell stability in keratinized OSCC and helped to characterize WD with MD/PD/WD with lymphadenopathy OSCC. Additionally, novel isoforms of IL37, NAA10, UCHL3, SPAG7, and RAB24 were identified while in silico functionally validated SPAG7 represented the premalignant phenotype of keratinized (K4) OSCC. Most importantly we found copy number gain and overexpression of EGFR suggest that TKIs may also be used as therapeutics in WD-OSCCs.


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