Date of Award

8-1-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Cancer Biology

Department

Graduate School of Biomedical Sciences

First Advisor

Jamboor K. Vishwanatha

Second Advisor

Alakananda Basu

Third Advisor

Rance Berg

Abstract

Migration and invasion enhancer 1 (MIEN1), a gene located in the 17q12 region of the human chromosome, enhances migratory and invasive potential of cancer cells via two mechanisms; activating the Akt dependent NF-κB downstream signaling and facilitating filopodia formation; thereby playing an important role in cancer progression. MIEN1 is highly expressed in many cancers including prostate and breast, but its expression is very basal to null in a variety of normal tissues making it a plausible target for cancer therapy. Though the functions of MIEN1 are known, the reasons for its increased expression in cancer is unknown. Determining the molecular gene regulatory mechanisms by which expression of MIEN1 is curtailed in normal cells will help in developing better targeting strategies.

Among the different gene regulatory mechanisms including transcriptional regulation, post-transcriptional modifications and histone and DNA alterations, here we focus on post transcriptional and DNA methylation based regulation of MIEN1. We show that MIEN1 is downregulated post-transcriptionally by miRNA-940 which itself is present in low amounts in cancer cells and tissues compared to the normal counterparts. The miR-940 also contributes to inhibition of cancer progression by attenuating the migration, invasion, anchorage-independent growth and epithelial-to-mesenchymal transition, when ectopically re-introduced into cancer cells. The miR-940 can be detected in circulation and its elevated levels in serum from cancer patients than normal subjects, suggest its potential as a biomarker for prostate cancer diagnosis. MIEN1, like urokinase plasminogen activator, is also suppressed by DNA methylation in normal cells. On the contrary, hypomethylation in cancer, results in its overexpression. The current approach of using global demethylating agents to activate the expression of hypermethylated tumor suppressor genes may in the long run activate tumor promoting genes like MIEN1. Thus, our study supports the notion that gene-centric hypomethylating agents may be a better epigenetic targeting approach to treat cancer. In conclusion, our data confirm the role of post-transcriptional and DNA methylation mediated mechanisms in the regulation of MIEN1.

Comments

Rajendiran, Smrithi, Post-transcriptional and Epigenetic Regulation of MIEN1 in Prostate Cancer. Doctor of Philosophy (Biomedical Sciences, Cancer Biology), July 2014, 177 pp., 2 tables, 32 illustrations, 269 references. Available online August 2016.

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