Research Interests: Human Molecular Genetics & Cancer Biology

The major research interests of my laboratory include
  • 1) cellular and molecular basis of oral squamous cell carcinoma (OSCC/oral cancer) with the aim of finding therapeutic targets, and
  • 2) next-generation sequencing based discovery of causative genes for the following genetic disorders: primary microcephaly (small brain), anencephaly (small or missing brain hemispheres), Parkinson’s disease and Wilson’s disease.

Currently, we are looking for motivated students to
  • 1) explore the role of microRNAs in OSCC with an aim to use them as therapeutic targets, and
  • 2) find transcriptional targets of the tumor suppressor TSC2 (tuberin) and their use in oral cancer therapeutics.

OSCC includes cancer of the lips, tongue, upper and lower gingivae, floor of the mouth, soft palate, cheek mucosa, vestibule of the mouth and retromolar trigone. In developing countries, it is the sixth most common cancer in males and tenth in females. In India, it is the leading cancer in males and the third most common malignancy in females. However, in spite of many advances in its treatment, there are still many lacunae in existing treatment strategies as a result of which the five-year survival rate of OSCC has remained unchanged during the last few decades. It is thus imperative to identify novel therapeutic targets for OSCC. Recent studies have shown that a growing class of non-coding RNAs called microRNAs (miRNAs) are involved in post-transcriptional regulation of genes. In human neoplasms, recent studies have shown deregulation of miRNA expression and the contribution of miRNAs to the multi-step process of tumorigenesis, either as oncogenes or tumor suppressor genes. In recent years, miRNAs have been used as therapeutic targets in several cancers. We have recently shown the utility of oncogenic miR-155 in OSCC as a therapeutic target in a preclinical trial, using xenografts in nude mice. Given this background, we will be exploring, identifying and exploiting the role and the use of miRNAs in oral cancer therapeutics, using a preclinical xenograft nude mouse model.

Mutations in the TSC2 gene cause an autosomal dominant disorder, tuberous sclerosis complex (TSC). TSC2 codes for a 200 kDa protein, which interacts with TSC1 and forms the TSC1/TSC2 complex. Mutations in the TSC1 gene also cause TSC. The TSC1/TSC2 complex negatively regulates mTOR in the PI3K-AKT-mTOR (insulin signalling) pathway (see Figure below) and in turn regulates cell proliferation. Both genes function as tumor suppressors. TSC1 localizes to the cytoplasm, but TSC2 shows nuclear as well as cytoplasmic localization. However, the nuclear function of TSC2 remains elusive. To identify the nuclear function of TSC2, we have recently performed a whole-genome expression profiling of TSC2 overexpressing cells, and the results showed differential regulation of 266 genes. EREG (epiregulin), a member of the epidermal growth factor family, was found to be the most downregulated gene in the microarray analysis. Using the luciferase reporter, ChIP and EMSA techniques, we showed that TSC2 binds to the EREG promoter between -352 bp to -303 bp and negatively regulates its expression. This was the first evidence for the nuclear function of TSC2 as a transcription factor and of TSC2 binding to the promoter of any gene. Based on the bioinformatics analysis, we were able to identify a conserved motif 5’GCCTTG3’ in the promoter of the EREG gene. However, we are not sure if it is indeed a TSC2 binding motif. We therefore plan to further explore and identify 1) other genes which are transcriptionally regulated by TSC2 and their role and utility as therapeutic targets in OSCC, and 2) the TSC2 DNA binding motif in promoters of EREG and other yet to be identified TSC2-regulated genes, using a variety of molecular biology based approaches such as ChIP, EMSA, siRNA, DNA footprinting, ChIP sequencing etc.

Created by Indu K. Jaishwal, 2010