During suddenly encountering mutation, turns against its own

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During my graduation, being in the microbiology department,
I explored many diseased states where an external organism was pathogenic to
our human body.  But, what amazed me was
how 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 the
deadly 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 of
research work related to understanding pancreatic carcinoma metastasis and drug
targeting to such cells. PDAC is a leading cause for cancer related death
worldwide. It is the most invasive of all the carcinomas and is very difficult
to treat. Majority of the problems are associated with poor treatment due to
the multi-drug resistance capacity of the PDAC cells.

MUC1 is a heavily glycosylated trans-membrane protein which
is expressed at the surface of epithelial cells and is seen to highly express
in malignancies, especially pancreatic cancer. It is also considered as a
potential biomarker for the same. The glycoprotein consists of three domains:
extracellular domain, hydrophobic trans-membrane domain and the cytoplasmic
tail domain (CTD) (Review, Nath et al,
2014). In normal epithelial cells, MUC1 helps in protection from bacterial
invasion and inflammation due to it o-glycosylated ecto-domain. In
malignancies, it is seen to be highly expressed and has roles involving signal
transduction using the ecto-domain as well as the cytoplasmic tail domain
(CTD). The CTD part of the protein localises to the nucleus to regulate
transcription of genes necessary for tumour progression. Overexpression of
MUC-1 also confers the multi -drug resistance to the PDAC cells. Hence, MUC1 is
a highly targeted molecule for understanding pancreatic malignancy.

Recently, it was discovered that MUC1 cross talks and
stabilizes HIF1-alpha which leads to transcription of HRE genes (Shukla et al. 2017). HIF1-alpha is a regulator
of glycolysis in hypoxic conditions. This results in increase in glucose uptake
due to higher expression of GLUT transporters (Review, Denko, 2008). As the conditions are hypoxic, Glucose is
converted to Pyruvate, which is then converted to lactate by the enzyme lactate
dehydrogenase. Previous studies have suggested that lactate has a major role in
cancer progression, and also maybe a potent regulator of some sort (Goodwin, 2014).

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The reason for up regulation of MUC1 protein on the surface
of cancer cells compared to that of normal epithelial cells is not known. My
hypothesis is that the excess production of lactate due to the hypoxic
condition further induces the up regulation of the MUC1 gene, resulting in much higher expression of MUC1 on malignant
cells. Hence, MUC1 cross talks and stabilizes HIF-1alpha to bring about its own
expression through lactate. Sp-1 is seen to be a transcriptional regulator for MUC1 (Morris et al. 2001). The genes for
lactate dehydrogenase (LDH) and sp-1 have a common regulator called Nrf2 which suggests some
relation between MUC1 and lactate, thus supporting my hypothesis.

To prove this hypothesis, pancreatic cancer cell Bx-PC3
line: Wild Type and lactate dehydrogenase (LDH) knockout variants, can be
generated under hypoxic conditions. MUC1
gene expression can be analysed using RT-qPCR in both the variants (presence
and absence of lactate). Similarly, studies can be conducted by providing
exogenous lactate to the LDH knockout to observe whether MUC1 protein
expression restores to the level of the wild type Bx-PC3 line. MUC1-GFP
reporter gene can be transfected into both the variants to visualise MUC1
protein expression and quantified. If the expression is dependent on lactate,
further studies on the mechanism of action can be carried out. Relation between
lactate and Sp-1 can be analysed to see how lactate might be indirectly
inducing gene expression.

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

Categories: Biology


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