CDLD Research Project 1: Epithelial Adherens Junctions Regulate Colon Cell Behavior Through RNAi and lncRNAs
Antonis Kourtidis Ph.D. – Department of Regenerative Medicine and Cell Biology
Kourtidis Lab Webpage
Although extensively studied, colon cancer is still the third most prevalent form of cancer. Pre-cancerous conditions in the colon, such as inflammatory bowel disease, are also on the rise. This implies that there are still gaps in our understanding of intestinal diseases. The recent identification of a large novel class of RNAs, called long non-coding RNAs (lncRNAs) has added a layer of complexity because several contribute to intestinal disease and cancer. However, our knowledge of lncRNA regulation and function as well as the extent of their contribution to the progression of these diseases is still very limited.
A common feature of intestinal diseases is loss of epithelial integrity. The adherens junctions are essential for normal epithelial tissue formation and maintenance. We have discovered a mechanism that links the integrity of adherens junctions with the RNA interference (RNAi) machinery and regulation of non-coding RNAs. This is a completely novel and unexpected finding that opened a new direction in the fields of cell adhesion and non-coding RNAs. We aim to extend this exciting new research in this proposed project. We have shown that PLEKHA7, a novel E-cadherin partner at the adherens junctions, recruits core components of the RNAi machinery, the microprocessor and the RNA-induced silencing complex (RISC), as well as sets of miRNAs and mRNAs. PLEKHA7 depletion results in compromised epithelial integrity, altered miRNA levels and function, and pro-tumorigenic cell transformation. We have also found widespread mis-localization or loss of PLEKHA7 in colon cancer cell lines and patient tissues. Our preliminary data reveal that PLEKHA7 also associates with a large set of lncRNAs and that depletion of PLEKHA7 results in altered levels of 49 of them. Provocatively, the most upregulated lncRNA upon PLEKHA7 depletion is MIR17HG (miR-17-92; OncomiR-1), a known oncogenic lncRNA that is overexpressed in colorectal cancers. LncRNAs can be regulated by miRNAs through RISC25-27. Our data further reveal that PLEKHA7 recruits and regulates lncRNAs, miRNAs and RISC at the adherens junctions.
We hypothesize that PLEKHA7 suppresses MIR17HG by recruiting RISC at the adherens junctions, to maintain colon epithelial homeostasis and to inhibit tumorigenesis (Figure 1).