Human Molecular Genetics & Cancer Biology
The major research interests of my laboratory include 1) cellular and molecular basis of oral cancer with an aim to find therapeutic targets, and 2) next-generation sequencing based discovery of causative genes for the following genetic disorders:primary microcephaly (small brain) and anencephaly (missing brain hemispheres). Currently, we are looking for motivated students to 1) explore the role of microRNAs in oral cancer 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.
In India, oral cancer is the leading cancer in males and the third 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 it. Recent 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 have been used as therapeutic targets in several cancers. Given this background, we wish to explore, identify and exploit the role and the use of microRNAs 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 protein 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, 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. Using gene expression profiling of TSC2 overexpressing cells, luciferase reporter assay, ChIP and EMSA techniques, we have recently shown that TSC2 also functions as a transcription factor and regulates the transcription of Epiregulin, a ligand for EGFR. We plan to further explore and identify other genes which are transcriptionally regulated by TSC2 and their role and utility as therapeutic targets in oral cancer.
- Singh N, Bhat VK, Tiwari A, Kodaganur SG, Tontanahal SG, Sarda A, Malini KV and Kumar A (2017). A homozygous mutation in TRIM36 causes autosomal recessive anencephaly in an Indian family. Human Molecular Genetics, DOI: 10.1093/hmg/ddx020.
- Tiwari A, Shivananda S, Gopinath KS and Kumar A (2014). microRNA-125a reduces proliferation and invasion of oral squamous cell carcinoma cells by targeting estrogen-related receptor alpha: implications for cancer therapeutics. Journal of Biological Chemistry, 289:32276-32290.
- Pradhan SA, Rather MI, Tiwari A, Bhat VK and Kumar A (2014). Evidence that TSC2 acts as transcription factor and binds to and represses the promoter of epiregulin. Nucleic Acids Research, 42:6243-6255.
- Rather MI, Nagashri MN, Swamy SS, Gopinath KS and Kumar A (2013). Oncogenic microRNA-155 down-regulates tumor suppressor CDC73 and promotes oral squamous cell carcinoma cell proliferation: implications for cancer therapeutics. Journal of Biological Chemistry, 288:608-618.
- Kumar A, Girimaji SC, Duvvari MR and Blanton SH (2009). Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly. American Journal of Human Genetics, 84:286-290.