The Oncogenic Function of PLAGL2 is Mediated Via ASCL2 and IGF2 and a Wnt-independent Mechanism in Colorectal Cancer

Overview

Journal Am J Physiol Gastrointest Liver Physiol

Publisher American Physiological Society

Specialties Gastroenterology
Physiology

Date 2023 Jun 13

PMID 37310750

Authors

Anthony D Fischer

Daniel A Veronese Paniagua

Shriya Swaminathan

Hajime Kashima

Deborah C Rubin

Blair B Madison

Affiliations

Soon will be listed here.

Abstract

Colorectal cancer (CRC) tumorigenesis and progression are linked to common oncogenic mutations, especially in the tumor suppressor , whose loss triggers the deregulation of TCF4/β-Catenin activity. CRC tumorigenesis is also driven by multiple epimutational modifiers such as transcriptional regulators. We describe the common (and near-universal) activation of the zinc finger transcription factor and Let-7 target PLAGL2 in CRC and find that it is a key driver of intestinal epithelial transformation. PLAGL2 drives proliferation, cell cycle progression, and anchorage-independent growth in CRC cell lines and nontransformed intestinal cells. Investigating effects of PLAGL2 on downstream pathways revealed very modest effects on canonical Wnt signaling. Alternatively, we find pronounced effects on the direct PLAGL2 target genes , a fetal growth factor, and , an intestinal stem cell-specific bHLH transcription factor. Inactivation of PLAGL2 in CRC cell lines has pronounced effects on ASCL2 reporter activity. Furthermore, ASCL2 expression can partially rescue deficits of proliferation and cell cycle progression caused by depletion of PLAGL2 in CRC cell lines. Thus, the oncogenic effects of PLAGL2 appear to be mediated via core stem cell and onco-fetal pathways, with minimal effects on downstream Wnt signaling. A Let-7 target called PLAGL2 drives oncogenic transformation via Wnt-independent pathways. This work illustrates the robust effects of this zinc finger transcription factor in colorectal cancer (CRC) cell lines and nontransformed intestinal epithelium, with effects mediated, in part, via the direct target genes ASCL2 and IGF2. This has implications for the role of PLAGL2 in activation of onco-fetal and onco-stem cell pathways, contributing to immature and highly proliferative phenotypes in CRC.

Citing Articles

Bioinformatics Analysis Identifies as the Key Transcription Factor in Hepatocellular Carcinoma Progression.

Zhang H, Zong R, Wu F, Li Y Dis Markers. 2023; 2023:3560340.

PMID: 36755802 PMC: 9902118. DOI: 10.1155/2023/3560340.

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