# The miR-20/c-Myc/E2F Regulatory Axis is Critical for the Tumor Promoting Activity of Inflammatory Fibroblasts in Colitis-Associated Cancer

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $555,555

## Abstract

SUMMARY
Inflammation is a risk factor for several types of cancer. For example, in ulcerative colitis (UC), a disease of
chronic inflammation of the colon, the risk of developing colitis-associated cancer of the colon (CAC) is 3 to 5-
fold higher than the risk in the general population of developing sporadic colorectal cancer (CRC). Worse, there
are no curative CAC-preventing or CAC-reversing options for UC patients, and the pathogenesis of CAC is
unclear. The precise oncogenic triggers in this complex milieu remain mysterious and are therefore difficult to
target. Given this situation, our long-term goal is to understand the pathogenesis of colitis and CAC such that
development of preventive interventions becomes more feasible. We recently reported that colitis-associated
fibroblasts and cancer-associated fibroblasts from UC patients secrete elevated levels of CXCL8 (an
inflammatory mediator), that CXCL8 levels are negatively regulated by a miRNA, miR-20a, and that miR-20a is,
at least in part, responsible for the modulation of CXCL8 secretion in interstitial fibroblasts. miR-20a is known to
be modulated by c-Myc via interaction with the E2F family of transcription factors. However, in contrast to the
colon epithelia our data indicate that low miR-20a and low c-Myc levels in colitic fibroblasts increase
tumorigenicity. To resolve this conundrum, the overall objective of this application, is to determine the
contribution of fibroblast miR-20, a member of the miR-17 family, to the pathogenesis of CAC. Our central
hypothesis is that downregulation of the miR-20a/c-Myc/E2F axis is critical for the tumor-promoting activity of
colon interstitial fibroblasts. To test these relationships, we will pursue three Aims: 1) To define the contribution
of miR-20 in the colitic stromal fibroblasts to tumorigenesis, 2) To delineate the roles of fibroblast c-Myc and
E2F7/8 on miR-20 and tumor-promotion, and 3) To identify the stromal fibroblast populations associated with
disease progression and to determine their use as prognostic tools. The approach is innovative as it uses
exclusively human tissue isolates, focuses on mechanistic investigation of the miR-20a, c-Myc, and E2F7/8
relationships, and reconciles fibroblast subpopulations at the single cell level for their contributions to the
pathogenesis of CAC. The research is significant as it provides a molecular basis for the tumor-promoting activity
of the stroma, which will benefit the one million US colitis patients at risk for CAC. In addition, our findings will
be applicable for any chronic inflammatory process for which the stroma provides additional avenues for
intervention.

## Key facts

- **NIH application ID:** 10388030
- **Project number:** 7R01CA237304-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Emina Hui-Na Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $555,555
- **Award type:** 7
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388030

## Citation

> US National Institutes of Health, RePORTER application 10388030, The miR-20/c-Myc/E2F Regulatory Axis is Critical for the Tumor Promoting Activity of Inflammatory Fibroblasts in Colitis-Associated Cancer (7R01CA237304-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10388030. Licensed CC0.

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