Unit:
Specialty Molecular Biomedicine Mechanisms of Disease, Molecular and Cellular Therapies, and BioinnovationLibrary of the School of Health Sciences
Author:
Galaras Alexandros
Supervisors info:
Παντελής Χατζής, Ερευνητής Β', ΕΚΕΒΕ Φλεμινγκ
Γεώργιος Κόλλιας, Καθηγητής, Ιατρικής, ΕΚΠΑ
Αντιγόνη Δήμα, Ερευνήτρια Γ', ΕΚΕΒΕ Φλεμινγκ
Original Title:
Investigating the role of WiNTRLINC3 in intestinal homeostasis and carcinogenesis
Translated title:
Investigating the role of WiNTRLINC3 in intestinal homeostasis and carcinogenesis
Summary:
The canonical Wnt pathway is an essential regulator of intestinal self-renewal, affecting the transcriptional profile of a plethora of genes involved in development, proliferation and stem cell maintenance. Functional perturbations of the Wnt pathway that result in aberrant activity of β-catenin, the main modulator of this signaling cascade, are among the leading causes of Colorectal Cancer (CRC). Interestingly, there is strong evidence that multiple targets of the effector β-catenin/TCF4 transcriptional complex reside in non-coding regions with several long non-coding RNAs (lncRNAs) operating either as regulators or as targets of the Wnt pathway, ultimately affecting intestinal physiology.
In our study we characterize WiNTRLINC3, a long intergenic non-coding RNA (lincRNA) which is negatively regulated by the β-catenin/TCF4 pathway and the low expression of which is associated with Colorectal Cancer. Cis-overexpression of WiNTRLINC3 with the use of CRISPRa system in the intestinal cell line LS174 showed that WiNTRLINC3 mainly increases the expression of genes that control cell adhesion facilitating cell differentiation, while it down-regulates genes that promote cell proliferation. Among the up-regulated genes, we distinguished IGSF9 as a putative mediator of the function of WiNTRLINC3. IGSF9 is a cell adhesion protein that is encoded by a gene located in the vicinity of WiNTRLINC3 and reduced expression of which also correlates with Colorectal Cancer. We report that WiNTRLINC3 and IGSF9 display a similar regulatory pattern, with WiNTRLINC3 controlling the expression of IGSF9, but not vice versa.
Moreover, we investigate the role of CDX2 transcription factor, a protein that was identified as interactor of WiNTRLINC3 in RNA pull-down experiments. in regulating WiNTRLINC3. Re-analysis of publicly available data in LS174 cells helped us determine the global binding pattern of CDX2. Among others, CDX2 strongly binds to both the promoter and an intronic enhancer of WiNTRLINC3, pointing to direct regulation of WiNTRLINC3 expression by CDX2. We are currently evaluating if the activity of those regulatory regions is elevated upon overexpression of CDX2. We speculate that CDX2 activates WiNTLINC3 by interacting with it, ultimately affecting the expression of IGSF9.
We propose that WiNTRLINC3 may be a biomarker and therapeutic target in colorectal cancer.
Main subject category:
Health Sciences
Keywords:
Cancer, CDX2, Wnt pathway, Gene regulation, IGSF9, lncRNAs
Number of references:
149
