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Hepatic Cell Biology

Hepatic Cell Biology

The major scientific   contributions are in the areas of signaling pathways that determine cellular fate in growth arrest vis a vis cellular transformation.  The key areas of scientific contribution include : (a) Unravelling the paradoxical roles of Sirtuin members (SIRT2 and SIRT7) in cellular senescence and proliferation, (b) Unfolded protein response as rejuvenating mechanisms preventing liver failure and its role in caner stem cells (c) Identification of Ras and Calcineurin signaling in viral induced carcinogenesis

Work from the Lab on the Cover- Page of Journals

Major Scientific Contributions:

Senescence and Cancer:  As ageing and cancer are at croosroads, the group has evaluated  mechanisms that can prevent cellular senescence and impact progression towards cancer. The group has investigated the role of mammalian Sirtuin family, , NAD+-dependent histone deactylase  in  cellular senescence  and  its impact on  cancer evolution. As there are seven different isoforms of Sirtuins (SIRT1-SIRT7) following significant contributions has been made on the cellular role of SIRT7 and SIRT2. Following are the key achievements:

  • Identification of  nuclear/ nucleolar targeting signals of SIRT7 and nucleolar  loss of SIRT7 in replicative senescence ( Kiran et al.,  FEBS J, 2013)
  •  Identified the role of  SIRT7 in altering cellular fate by preventing premature senescence via attenuating DNA damage response by regulating p53 response together with modulation of Stress Activated Protein Kianses activation ( Kiran et al.,  Expt Cell Res 2015).
  • Identified a role of SIRT7 in Epithelial to Mesenchymal Transition with relevance to metastatic cell in homing ( Kiran et al, Frontiers in Oncology, 2020)
  • SIRT2  was  identified  as a senescence associated marker (Anwar et al, Cell Cycle, 2016,  Investigator award to student, Tarique, Cell Biology Meeting) , which is now currently been used to identify senescent hepatocytes in patients suffering from end stage liver disease or cirrhosis.
  • Specific increase in levels of SIRT1 in cervical intraepithelial lesions make it a promising candidate for identification of preneoplastic changes in cancer cervix (Singh et al., Tumor Biol, 2015). 
  • Accumulation of senescent cell in end stage liver diseases and  involvement of mitochondrial unfolded protein response in ameliorating senescence ( Bijoya Sen et al, Cellular and Molecular Gastroenterology and Hepatology, 2019; On the Cover Page of CMGH,  Young Investigator Award at AASLD)
  • Senescent cells are inflammatory in nature and their presence in cancerous milieu leads to alterations in immune cell fate (Sen et al, under review).

Peroxovanadates as effective tools to induce stress induced premature senescence

In continuation of the previous studies on  ageing,  Dr. Gayatri Ramakrishna’s work has led to  identification of  diperoxovanadate as more  effective  tool, than the most widely used H2O2 in inducing premature senescence. 

  • Peroxovandates could act at much lower concentrations  than H2O2 and were also more efficient in inducing senescent phenotype (Chatterjee et al, Mechanism of Ageing and Development, 2013). 
  • The work has also provided novel insights on the senescent-inducing role of peroxovanadates by activation of Rac1-NADPH oxidase leading to oxidative stress and DNA damage (Chatterjee et al, Molecular and Cellular Biochemistry, 2016).

Signaling pathways during neoplastic transformation:

  • Dr. Gayatri Ramakrishna had  previously proposed a role of wild type Ras in growth arrest     (Singh et al, FASEB J, 2013)     And  this was supported by the observation on  significantly low amounts of wild type Ras-p21 in hepatocellular carcinoma       (Bose et al., Journal of   Gastroenterology  and Hepatology, 2011). These results have suggested a novel role of growth suppressive effects for the wild type Ras.  A stochastic model for progression of hepatic cancer was proposed.   
  • Yet another major contribution is the identification of calcineurin signalling in cervical cancer. The work has unraveled activation of calcineurin-NFAT2 activation in cervical cancer by the oncoprotein of Human Pappiloma Virus ( Ram et al, Exp Cell Res, 2017) and further blocking this pathway using calcieurin inhibitor, cyclosporine A, resulted in non-apoptotic form of cell death in cancer cells.  (Ram et al, BBA: Molecular Cell Res , 2014). This work has opened a new avenues for exploiting non-apoptotic forms as new drug  target in cancer therapeutics, especially for neoplastic cells  resistant to apoptosis such as liver cancer.
  • In a collaborative work with Dr. Nirupma’s group (ILBS), progress was made in identification of EpCAM positive cancer stem cells in hepatocellular carcinoma  and further the role of micro RNA (miR-26b-5p )was elucidated in regulating both the  Heatshock protein HPA8 and EpCAM ( Khosla et al, Liver International 2019; Khosla et al., Stem Cells Transl Med, 2017).
  • In a collaborative work with Dr. Sanjeev Khosla (CDFD),  role of  DNMT3L gene hypermethylation as a potential marker of cancer cervix progression was identified  (Gokul et al,  Epigenetics, 2007 and 2009).

Cervical cancer screening programme and identification of epigenetic  marker in cervical cancer progression:

  • Dr. Gayatri Ramakrishna has collaborated with a team of epidemiologists and clinicians in a major cancer screening programme in rural Andhra Pradesh.  Her group was involved in detection of Human pappilomavirus (HPV),  in cervical samples, which is an etiologial risk factor for cancer cervix progression. A concerted group effort lead to  HPV screening of close to 2300 women attending the cancer detection clinic of a rural  hospital at Medchal Mandal near Hyderabad in Telengana. A part of this work has been published and is one of the mostly highly accessed and cited work (Sowjanya, P. et al, BMC Infectious Disease, 2005;  ).

Images of Chemotherapy Induced Senescence

Taken from our published work : Sen et al, CMGH, 2020

Generation of Stable Hepatoma Cell Line expressing Mitochondrial Protease, ClpP

Taken from our published work : Sen et al, CMGH, 2020

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