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Institute of Molecular Medicine

Laboratory of Devanand Sarkar, M.B.B.S, Ph.D.

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Research projects

The research in Dr. Sarkar’s laboratory focuses on understanding the molecular mechanism of carcinogenesis and developing novel, targeted anti-cancer therapy based on the garnered knowledge.

The cancer model used is primarily hepatocellular carcinoma (HCC) since there is a worldwide epidemic of HCC and, unlike other cancers, the incidence of HCC in Western countries is rising. The mortality of HCC parallels its incidence, since it is highly resistant to standard radio- and chemotherapy. Understanding the molecular mechanism of HCC will facilitate development of novel, targeted therapies to counteract this fatal malady.

Recent studies in the lab reveal that the oncogene astrocyte elevated gene-1 (AEG-1) is overexpressed at mRNA and protein levels in more than 90 percent of HCC patients, and in a subset of patients, the AEG-1 gene itself is amplified. Overexpression of AEG-1 in poorly aggressive, non-tumorigenic HCC cells results in highly aggressive angiogenic and metastatic tumors in nude mice. Conversely, siRNA inhibition of AEG-1 in highly aggressive HCC cells significantly retards in vivo tumorigenesis, angiogenesis and metastasis.

AEG-1 activates multiple pro-tumorigenic signal transduction pathways, such as NF-ĸB, PI3K/Akt, MEK/ERK and Wnt, and it profoundly modulates global gene and protein expression profiles, leading to changes in expression of proteins regulating proliferation, cell cycle, invasion, angiogenesis, chemoresistance, metastasis and senescence.

AEG-1 is a protein with a transmembrane domain, multiple nuclear localization signals and no other known domains or motifs. It is localized in the cell membrane, nucleus and nucleolus, cytoplasm and ER. In each localization, AEG-1 interacts with specific proteins that confer the pleiotrophic properties to AEG-1. It is suggested that AEG-1 might be a scaffold protein favoring formation of multi-protein complexes.

Dr. Sarkar’s group is trying to understand the molecular mechanism of AEG-1’s function by identifying its downstream genes/proteins (determined by Affymetrix microarray and proteomic analyses) and interacting proteins (determined by yeast two-hybrid assay and co-immunoprecipitation followed by mass spectrometry), and by analyzing transgenic mice with hepatocyte-specific overexpression of AEG-1 and conditional knockout mice of AEG-1.

Laboratory members

Maaged Akiel
Graduate Student

Nidhi Himanshu Jariwala
Graduate Student

Saranya Chidambaranathan-Reghupaty
Graduate Student

Chadia Robertson
Postdoctoral Fellow

Rachel Mendoza
Laboratory and Research Manager

Key publications

Rajasekaran D, Jariwala N, Mendoza RG, Robertson CL, Akiel MA, Dozmorov M, Fisher PB, Sarkar D. Staphylococcal nuclease and tudor domain containing 1 (SND1) promotes hepatocarcinogenesis by inhibiting monoglyceride lipase (MGLL). J Biol Chem. 2016, 291: 10736-10746.

Akiel MA, Santhekadur PK, Mendoza RG, Siddiq A, Fisher PB, Sarkar D. Tetraspanin 8 (TSPAN8) mediates AEG-1-induced invasion and metastasis in hepatocellular carcinoma (HCC) cells. FEBS Lett. 2016, 590: 2700-8.

Srivastava J, Siddiq A, Gredler R, Shen X-N, Rajasekaran D, Robertson CL, Subler MA, Windle JJ, Dumur CI, Mukhopadhyay ND, Garcia D, Lai Z, Chen Y, Balaji U, Fisher PB, Sarkar D. Astrocyte elevated gene-1 and c-Myc cooperate to promote hepatocarcinogenesis in mice. Hepatology. 2015, 61: 915-929. (Highlighted in the Editorial of Hepatology).

Rajasekaran D, Siddiq A, Willoughby JLS, Biagi JM, Christadore LM, Yunes SA, Gredler R, Jariwala N, Robertson CL, Akiel MA, Shen X-N, Subler MA, Windle JJ, Schaus SE, Fisher PB, Hansen U, Sarkar D. Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): evaluation using an endogenous HCC model. Oncotarget. 2015, 6: 26266-26277.

Robertson CL, Srivastava J, Siddiq A, Gredler R, Emdad L, Rajasekaran D, Akiel MA, Shen XN, Corwin F, Sundaresan G, Zweit J, Croniger C, Gao X, Ghosh S, Hylemon PB, Subler MA, Windle JJ, Fisher PB, Sarkar D. Astrocyte elevated gene-1 (AEG-1) regulates lipid homeostasis. J Biol Chem. 2015, 290: 18227-18236.

Srivastava J, Robertson CL, Gredler R, Siddiq A, Rajasekaran D, Akiel MA, Emdad L, Mas V, Mukhopadhyay ND, Fisher PB, Sarkar D. Astrocyte elevated gene-1 (AEG-1) contributes to nonthyroidal illness syndrome (NTIS) associated with hepatocellular carcinoma (HCC). J Biol Chem. 2015, 290: 15549-15558.

Rajasekaran D, Srivastava J, Ebeid K, Gredler R, Akiel MA, Jariwala N, Robertson CL, Shen XN, Siddiq A, Fisher PB, Salem AK, Sarkar D. Combination of nanoparticle-delivered siRNA for Astrocyte elevated gene-1 (AEG-1) and all-trans retinoic acid (ATRA): an effective therapeutic strategy for hepatocellular carcinoma (HCC). Bioconjug. Chem. 2015, 26:1651-1661.

Robertson CL, Srivastava J, Siddiq A, Gredler R, Emdad L, Rajasekaran D, Akiel M, Shen X-N, Guo C, Giashuddin S, Wang X-Y, Ghosh S, Subler MA, Windle JJ, Fisher PB, Sarkar D. Genetic deletion of AEG-1 prevents hepatocarcinogenesis. Cancer Res. 2014, 74: 6184-93. (Cover of Cancer Research).

Srivastava J, Robertson CL, Rajasekaran D, Gredler R, Siddiq A, Emdad L, Mukhopadhyay ND, Ghosh S, Hylemon PB, Gil G, Shah K, Bhere D, Subler MA, Windle JJ, Fisher PB, Sarkar D. AEG-1 regulates retinoid X receptor and inhibits retinoid signaling. Cancer Res. 2014, 74: 4364-4377.

Santhekadur PK, Akiel MA, Emdad L, Gredler R, Srivastava J, Rajasekaran D, Robertson CL, Mukhopadhyay ND, Fisher PB, Sarkar D. Staphylococcal Nuclease Domain Containing-1 (SND1) promotes migration and invasion via Angiotensin II Type 1 Receptor (AT1R) and TGFb signaling. FEBS Open Bio. 2014, 4: 353–361.

Chen D, Siddiq A, Emdad L, Rajasekaran D, Gredler R, Shen X-N, Santhekadur PK, Srivastava J, Robertson CL, Dmitriev I, Kashentseva EA, Curiel DT, Fisher PB, Sarkar D. Insulin-like growth factor binding protein-7 (IGFBP7): a promising gene therapeutic for hepatocellular carcinoma (HCC). Mol Ther. 2013, 21: 758-766.

Srivastava J, Siddiq A, Emdad L, Santhekadur P, Chen D, Gredler R, Shen X-N, Robertson CL, Dumur CI, Hylemon PB, Mukhopadhyay ND, Bhere D, Shah K, Ahmad R, Giashuddin S, Stafflinger J, Subler MA, Windle JJ, Fisher PB, Sarkar D. Astrocyte elevated gene-1 (AEG-1) promotes hepatocarcinogenesis: novel insights from a mouse model. Hepatology. 2012, 56: 1782-1791.

Santhekadur PK, Gredler R, Chen D, Siddiq A, Shen X-N, Das SK, Emdad L, Fisher PB, Sarkar D. LSF (Late SV40 Factor) enhances angiogenesis by transcriptionally upregulating matrix metalloproteinase-9 (MMP-9). J Biol Chem. 2012, 287: 3425-3432.

Santhekadur PK, Das SK, Gredler R, Chen D, Srivastava J, Robertson CL, Baldwin AS jr, Fisher PB, Sarkar D. Multifunction protein Staphylococcal Nuclease Domain Containing-1 (SND1) promotes tumor angiogenesis in human hepatocellular carcinoma through novel pathway that involves NF-kB and miR-221. J Biol Chem. 2012, 287: 13952-13958.

Yoo BK, Santhekadur PK, Gredler R, Chen D, Emdad L, Bhutia SK, Pannell L, Fisher PB, Sarkar D. Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinoma. Hepatology. 2011, 53: 1538-1548.

Chen D, Yoo BK, Santhekadur PK, Gredler R, Bhutia SK, Das SK, Fuller C, Su Z-Z, Fisher PB, Sarkar D. Insulin-like growth factor binding protein-7 (IGFBP7) functions as a potential tumor suppressor in hepatocellular carcinoma (HCC). Clin Cancer Res. 2011, 17: 6693-6701.

Yoo BK, Gredler R, Chen D, Santhekadur PK, Fisher PB, Sarkar D. c-Met activation through a novel pathway involving osteopontin mediates oncogenesis by the transcription factor LSF. J Hepatol. 2011, 55: 1317-1324.

Yoo BK, Emdad L, Gredler R, Fuller C, Dumur CI, Jones KH, Jackson-Cook C, Su Z-Z, Chen D, Saxena UH, Hansen U, Fisher PB, Sarkar D. The transcription factor LSF functions as an oncogene in hepatocellular carcinoma. Proc Natl Acad Sci USA. 2010, 107: 8357-62.

Yoo BK, Chen D, Su Z-Z, Gredler R, Shah K, Fisher PB, Sarkar D. Molecular mechanism of chemoresistance by Astrocyte elevated gene-1 (AEG-1). Cancer Res. 2010, 70: 3249-3258.

Yoo BK, Emdad L, Su Z-Z, Villanueva A, Chiang DY, Mukhopadhyay ND, Mills AS, Waxman S, Fisher RA, Llovet JM, Fisher PB, Sarkar D. Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J Clin Invest. 2009, 119: 465-477.

Yoo BK, Gredler R, Vozhilla N, Su Z-Z, Chen D, Forcier T, Shah K, Saxena U, Hansen U, Fisher PB, Sarkar D. Identification of genes conferring resistance to 5-fluorouracil. Proc Natl Acad Sci USA. 2009, 106: 12938-12943.

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