# TIMP1 as a context-dependent biomarker linking cancer progression and cardiovascular disorders: a multi-level and bioinformatics study

## TL;DR

TIMP1 is a key protein involved in cancer and heart disease, showing different roles depending on the disease context and offering potential for diagnosis and treatment.

## Contribution

TIMP1 is identified as a context-dependent biomarker linking cancer and cardiovascular disorders through multi-level and bioinformatics analysis.

## Key findings

- TIMP1 is upregulated in colorectal and gastric cancers, correlating with poor survival and high diagnostic accuracy.
- TIMP1 expression in cancer is linked to genomic alterations and promoter hypomethylation in digestive cancers.
- TIMP1 shows elevated levels in atherosclerosis and reduced levels in heart failure, indicating diverse cardiovascular roles.

## Abstract

Tissue inhibitor of metalloproteinase 1 (TIMP1) plays diverse roles in extracellular matrix (ECM) remodeling, immune regulation, and tumor progression. However, its systemic patterns across cancers and cardiovascular disease remain incompletely understood.

We applied an integrative pipeline beginning with microarray analysis of tumor-bearing mouse hearts (GSE63032) to identify TIMP1 as a hub gene. Pan-cancer datasets from TCGA/GTEx and public portals were analyzed for expression, genomic alterations, epigenetic regulation, immune infiltration, prognosis, and drug sensitivity. Single-cell RNA-seq was used to define cell type–specific expression. As all large-scale analyses were performed using publicly available bioinformatics datasets, cell line experiments were used for targeted validation of TIMP1 expression and function. Findings were validated by immunohistochemistry, western blotting, and transwell assays in colorectal and gastric cancer models, with additional analysis performed in atherosclerosis cohort (GSE100927) and heart failing cohort (GSE5406) to explore cardiovascular relevance.

TIMP1 was consistently upregulated across cancers, especially in colorectal and gastric tumors, where it correlated with adverse survival and high diagnostic accuracy. Genomic analyses revealed copy number alterations, while promoter hypomethylation aligned with increased expression in digestive cancers. Drug-response profiling indicated sensitivity to epigenetic inhibitors and resistance to MAPK-targeted agents. Single-cell analyses localized TIMP1 to myeloid cells in colorectal cancer and fibroblasts in gastric cancer, linking it to apoptosis, EMT, angiogenesis, and stromal–immune crosstalk. Beyond oncology, TIMP1 was elevated in atherosclerosis, aligning with immune- and lipid-related pathways, but reduced in heart failure, where it was linked to impaired mitochondrial metabolism.

This multi-level and bioinformatics study identifies TIMP1 as a cross-disease regulator with context-dependent functions. TIMP1 serves as a potential prognostic and diagnostic biomarker in digestive cancers, a therapeutic stratification marker for epigenetic interventions, and a candidate mediator linking tumor biology with cardiovascular disorders such as atherosclerosis and heart failure.