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Journal of Gastrointestinal & Digestive System | ISSN: 2161-069X | Volume: 8

&

&

October 29-30, 2018 | San Francisco, USA

International Conference on

Gastrointestinal Cancer and Therapeutics

4

th

World Congress on

Digestive & Metabolic Diseases

26

th

Annual Congress on

Cancer Science and Targeted Therapies

Regulation of calcium-sensing receptor expression by vitamin D and proinflammatory cytokines in

colorectal cancer

Irfete S Fetahu

Brigham and Women's Hospital, USA

A

nti-proliferative effects of calcium in the colon are partially mediated by the calcium-sensing receptor (

CaSR

). The

CaSR

gene is located in the chromosomal region 3q13.3-21 and is constituted of 2 non-coding and 6 coding exons.

The transcription of

CaSR

is under the control of promoters 1 and 2, which yield different transcripts containing either of

the untranslated exons 1A or 1B. The expression of

CaSR

decreases during colorectal tumorigenesis and the underlying

mechanisms regulating its expression are poorly understood. The

CaSR

promoters 1 and 2 harbor vitamin D elements

responsive to 1,25-dihydroxyvitamin D3 (1,25-D3) and NF-kB, STAT, and SP1 binding sites accounting for responsiveness

to proinflammatory cytokines. Vitamin D is known for its pro-apoptotic and anti-inflammatory effects in CRC. We have

previously shown that high dietary doses of vitamin D prevented the formation of chemically-induced preneoplastic lesions in

a mouse model. On contrary, increased production of proinflammatory cytokines, including TNFa and IL-6 has been reported

in inflammatory bowel disease and CRC patients. The impact of 1,25-D3 and proinflammatory cytokines (IL-6, TNFa) on

CaSR

expression in colon cancer cells is not well known. This led us to hypothesize that they might regulate the expression of

the

CaSR

. We performed a study where we analyzed the role of 1,25-D3, TNFa, and IL-6 on

CaSR

expression in Caco2/AQ,

a well differentiated and Coga1A, a moderately differentiated colorectal cancer cell line. Over the time course of 48 hours,

we observed upregulation of the

CaSR

expression in both cell lines. The well-differentiated Caco2/AQ cells responded with

higher induction of the

CaSR

expression than Coga1A cell line. Moreover, we observed a reduction in the expression of the

proliferation markers cyclin D1, minichromosome maintenance 2&7 (MCM2 and MCM7) in Caco2/AQ cells. These studies

suggested that in addition to the direct role of vitamin D in chemoprevention, it can also upregulate the expression of the

CaSR

,

thereby linking together the chemopreventive actions of vitamin D and calcium in colorectal tumors. In the less differentiated

cell line Coga1A, TNFa had a pronounced effect in increasing the expression of the

CaSR

, indicating that

CaSR

might serve as

a defense mechanism towards inflammatory stimuli. Additionally, in both cell lines, IL6 induced the expression of the

CaSR

.

Interestingly, in the well-differentiated Caco2/AQ cells treated with 1,25-D3 counteracted the effects of IL6 and TNFa. This

could be attributed probably to the anti-inflammatory role of the 1,25-D3. This study provides further evidence towards the

protective role of the

CaSR

in colon cells against inflammation.

Biography

Irfete S Fetahu received her PhD at the Medical University of Vienna (Austria) under the supervision of Prof Enikö Kallay as a Marie Curie Early Stage Researcher.

During this time she was the recipient of several national and international awards, including fellowships from the European Association for Cancer Research and

the Federation of European Biochemical Societies. She was a board member of the Young Scientist Association of the Medical University of Vienna. Following

her PhD graduation, she started her postdoctoral fellowship at the Harvard Medical School (USA), where she is currently working in uncovering the aberrancies

in the epigenomes of Alzheimer’s disease and melanoma. She is also a board member of the Harvard Medical Postdoc Association. She currently serves as an

Ambassador of the European Association for Cancer Research.

ifetahu@bwh.harvard.edu

Irfete S Fetahu, J Gastrointest Dig Syst 2018, Volume 8

DOI: 10.4172/2161-069X-C8-085