The major research interests of our laboratory include 1) cellular and molecular basis of oral, liver and lung cancers with the aim of finding therapeutic targets, and 2) next-generation sequencing based discovery of causative genes for genetic disorders such as primary microcephaly, Isolated microspherophakia, anencephaly, tuberous sclerosis complex, Wilson disease, etc. Currently, we are focusing on the following projects.

Identification of TSC2-regulated protein coding and non-coding RNA genes:

Mutations in tumor suppressor TSC1 and TSC2 genes cause an autosomal dominant disorder, tuberous sclerosis complex (TSC). TSC1 and TSC2 proteins interact to form a complex, which negatively regulates mTORC1 in the PI3K-AKT-mTOR pathway, and in turn regulates cell proliferation. This is a well-known cytoplasmic function of these TSC genes. We and others have shown earlier that TSC1/hamartin localizes to the cytoplasm, whereas TSC2/tuberin shows nuclear as well as cytoplasmic localization. To elucidate the nuclear function of TSC2, we have used gene expression profiling of TSC2-overexpressing cells, luciferase reporter assay, siRNA knockdown, ChIP and EMSA techniques, and have shown for the first time that TSC2 also functions as a transcription factor and transcriptionally regulates Epiregulin, a ligand for EGFR. However, Epiregulin (EREG) cannot be the only TSC2-regulated gene. Then, what are the other TSC2-regulated genes? We are thus exploring and identifying other (protein coding, microRNA and long non-coding RNA) genes, which are transcriptionally regulated by TSC2, using a variety of molecular and cell biology approaches such as microRNA microarray analysis, RNA-Seq, etc.

Identification of epigenetically-silenced microRNAs in oral cancer:

In India, oral cancer is the leading cancer in males and the fourth most common malignancy in females. However, in spite of many advances in its treatment, the 5-year survival rate for oral cancer has remained unchanged during the last few decades. It is thus imperative to identify novel therapeutic targets for oral cancer. Studies have shown deregulation of microRNA expression and the contribution of microRNAs to the multi-step process of tumorigenesis, either as oncogenes or tumor suppressor genes. In recent years, microRNAs are being used as therapeutic targets in cancers. Given this background, we are identifying and investigating the role and function of epigenetically silenced tumor suppressor miRNAs in oral cancer, with the aim to exploit them as therapeutic targets, using a variety of molecular cell biology techniques, including oral tumor samples from patients and preclinical xenograft nude mice model.

Molecular consequences of mutations in ATP7B, coding for a copper transporter:

Wilson disease (WD) is an autosomal recessive disorder, characterized by excessive deposition of copper in various parts of the body, mainly in the liver and brain. It is caused by mutations in ATP7B, which codes for a trans-Golgi network residing copper transporter. We have recently performed the genetic analysis of 102 WD families from a south Indian population, and identified 36 different ATP7B mutations, including 13 novel ones. However, the molecular consequences of these mutations in disease pathology are not known. Using a variety of molecular and cell biology approaches, we are interested to explore and identify the role of these novel ATP7B mutations in disease pathology. The work will also involve the use of specific inhibitor(s) to restore the function of mutated ATP7B, with an aim to develop therapeutic treatment for WD.