# Epithelial adherens junctions regulate colon cell behavior through RNAi and lncRNAs

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $331,833

## Abstract

PROJECT SUMMARY
Compromised epithelial integrity is a hallmark of gastrointestinal abnormalities, such as inflammatory bowel
disease and colon cancer, which is the third most prevalent and second most lethal form of cancer. The high
incidence rates of these diseases suggest that we still don’t fully understand the underlying mechanisms.
Recently, we discovered a mechanism that links epithelial tissue integrity with the RNA interference (RNAi)
machinery and with miRNA regulation. We have shown that the adherens junctions, which is an essential
architectural component of the cell, recruit the microprocessor and the RNAi-induced silencing complex (RISC),
the core components of the RNAi machinery, as well as a specific set of miRNAs, in colon epithelial cells. This
interaction occurs through PLEKHA7, a novel partner of the E-cadherin cell-cell adhesion complex. PLEKHA7
loss results in compromised epithelial integrity, decreased levels and function of a set of miRNAs and in
increased anchorage-independent growth, an indicator of epithelial transformation. Our preliminary data show
extensive mis-localization or loss of PLEKHA7 in colon cancer cell lines and tumor patient samples. Interestingly,
an RNA-CLIP experiment followed by RNA sequencing revealed association of PLEKHA7 with long non-coding
RNAs (lncRNAs). LncRNAs can interact with miRNAs and the RNAi machinery in multiple ways and a number
of them has been implicated in intestinal diseases. However, our knowledge on lncRNA regulation and function
is still limited. Our preliminary data show that PLEKHA7 loss results in altered expression of a number of these
lncRNAs, including upregulation of MIR17HG, a known promoter of cellular transformation. We hypothesize that
the adherens junctions recruit and regulate the RNAi machinery and lncRNAs to maintain colon epithelial
homeostasis. We will test our hypothesis in two Aims that will determine whether: 1) PLEKHA7 suppresses
MIR17HG levels through RISC and miRNAs at adherens junctions; 2) PLEKHA7 maintains the normal colon
epithelial phenotype through miRNAs and MIR17HG. This study is significant, since it provides a missing
mechanistic link between epithelial architecture and cell behavior and a new unexpected localized regulation of
RNAi and lncRNAs. The proposed work is innovative, because it tethers two previously unrelated fields, cell-cell
adhesion and non-coding RNA biology. The impact of the study is that it will advance our understanding of the
underlying mechanistic causes of intestinal diseases and will lay the foundation for the systematic interrogation
of the newly discovered connection between the adherens junctions, the RNAi machinery and non-coding RNAs.

## Key facts

- **NIH application ID:** 10378682
- **Project number:** 5R01DK124553-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Antonis Kourtidis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $331,833
- **Award type:** 5
- **Project period:** 2021-03-26 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378682

## Citation

> US National Institutes of Health, RePORTER application 10378682, Epithelial adherens junctions regulate colon cell behavior through RNAi and lncRNAs (5R01DK124553-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10378682. Licensed CC0.

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