TDGF1 drives colon cancer progression via Nodal/Smad2 and MAPK/AKT, linked to immunosuppression and poor survival.

The precise and multifaceted oncogenic role of teratocarcinoma-derived growth factor 1 (TDGF1) in colon cancer remains incompletely understood, despite its known involvement in various cancers. Current therapeutic strategies for advanced colon cancer often face challenges due to tumor heterogeneity and resistance mechanisms, highlighting the urgent need for novel prognostic biomarkers and effective therapeutic targets. Understanding the complex regulatory networks, such as competing endogenous RNA (ceRNA) axes, that govern TDGF1 expression could unlock new avenues for intervention in this aggressive disease.

Researchers conducted integrative bioinformatic and functional analyses to identify a novel ceRNA axis. In vitro experiments utilized colon cancer cell lines to assess the impact of the OLMALINC/miR-3614-5p/TDGF1 axis on cell proliferation, migration, invasion, and anti-apoptosis. For in vivo validation, TDGF1 knockdown was performed in an animal model to evaluate its effect on tumor growth. Mechanistic studies investigated signaling pathways. Additionally, transcriptomic and single-cell analyses characterized the tumor microenvironment, and a tissue microarray cohort was used to correlate TDGF1 expression with clinical parameters.

A novel competing endogenous RNA (ceRNA) axis was identified where the long non-coding RNA OLMALINC directly sponges hsa-miR-3614-5p, leading to the derepression of TDGF1. This OLMALINC/miR-3614-5p/TDGF1 axis significantly promoted colon cancer cell proliferation, migration, invasion, and anti-apoptosis in vitro. In vivo, TDGF1 knockdown significantly suppressed tumor growth. Mechanistically, TDGF1 co-activated oncogenic signaling via the Thr88-dependent Nodal/Smad2 cascade and the Glypican-1-mediated MAPK/AKT pathway. Beyond cell-autonomous effects, transcriptomic and single-cell analyses revealed that elevated TDGF1 correlates with an immunosuppressive microenvironment, characterized by reduced immune infiltration and altered LGALS9-CD44 malignant-T cell communication. Clinically, high TDGF1 expression in a tissue microarray cohort was significantly associated with advanced T stage, reduced expression of specific mismatch repair proteins (MLH1/PMS2), and poor overall survival.

High TDGF1 expression was significantly associated with advanced T stage, reduced MLH1/PMS2 expression, and poor overall survival in a clinical cohort.