During suddenly encountering mutation, turns against its own

During my graduation, being in the microbiology department,I explored many diseased states where an external organism was pathogenic toour human body.  But, what amazed me washow our own human cell can also turn pathogenic to us. A normal human cell,suddenly encountering mutation, turns against its own and gives rise to thedeadly state of cancer.

My major interest lies in the field of cancer biology,mainly pancreatic ductal Adenocarcinoma (PDAC). I would like to be a part ofresearch work related to understanding pancreatic carcinoma metastasis and drugtargeting to such cells. PDAC is a leading cause for cancer related deathworldwide. It is the most invasive of all the carcinomas and is very difficultto treat.

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Majority of the problems are associated with poor treatment due tothe multi-drug resistance capacity of the PDAC cells. MUC1 is a heavily glycosylated trans-membrane protein whichis expressed at the surface of epithelial cells and is seen to highly expressin malignancies, especially pancreatic cancer. It is also considered as apotential biomarker for the same. The glycoprotein consists of three domains:extracellular domain, hydrophobic trans-membrane domain and the cytoplasmictail domain (CTD) (Review, Nath et al,2014). In normal epithelial cells, MUC1 helps in protection from bacterialinvasion and inflammation due to it o-glycosylated ecto-domain. Inmalignancies, it is seen to be highly expressed and has roles involving signaltransduction using the ecto-domain as well as the cytoplasmic tail domain(CTD). The CTD part of the protein localises to the nucleus to regulatetranscription of genes necessary for tumour progression. Overexpression ofMUC-1 also confers the multi -drug resistance to the PDAC cells.

Hence, MUC1 isa highly targeted molecule for understanding pancreatic malignancy. Recently, it was discovered that MUC1 cross talks andstabilizes HIF1-alpha which leads to transcription of HRE genes (Shukla et al. 2017).

HIF1-alpha is a regulatorof glycolysis in hypoxic conditions. This results in increase in glucose uptakedue to higher expression of GLUT transporters (Review, Denko, 2008). As the conditions are hypoxic, Glucose isconverted to Pyruvate, which is then converted to lactate by the enzyme lactatedehydrogenase.

Previous studies have suggested that lactate has a major role incancer progression, and also maybe a potent regulator of some sort (Goodwin, 2014). The reason for up regulation of MUC1 protein on the surfaceof cancer cells compared to that of normal epithelial cells is not known. Myhypothesis is that the excess production of lactate due to the hypoxiccondition further induces the up regulation of the MUC1 gene, resulting in much higher expression of MUC1 on malignantcells. Hence, MUC1 cross talks and stabilizes HIF-1alpha to bring about its ownexpression through lactate.

Sp-1 is seen to be a transcriptional regulator for MUC1 (Morris et al. 2001). The genes forlactate dehydrogenase (LDH) and sp-1 have a common regulator called Nrf2 which suggests somerelation between MUC1 and lactate, thus supporting my hypothesis.

To prove this hypothesis, pancreatic cancer cell Bx-PC3line: Wild Type and lactate dehydrogenase (LDH) knockout variants, can begenerated under hypoxic conditions. MUC1gene expression can be analysed using RT-qPCR in both the variants (presenceand absence of lactate). Similarly, studies can be conducted by providingexogenous lactate to the LDH knockout to observe whether MUC1 proteinexpression restores to the level of the wild type Bx-PC3 line. MUC1-GFPreporter gene can be transfected into both the variants to visualise MUC1protein expression and quantified. If the expression is dependent on lactate,further studies on the mechanism of action can be carried out. Relation betweenlactate and Sp-1 can be analysed to see how lactate might be indirectlyinducing gene expression.

Establishment of this regulation can help us find ways oftackling multi drug resistance, as only when we understand the process, can weproceed to tackle it. 


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