TIMP2 is associated with prognosis and immune infiltrates of gastric and colon cancer

Fang, Jian; Yanhong, Jiao; Limeng, Wei; Niu, Guoping; Tian, Yue; Lin, Haiyan; Pan, Zhaoji

doi:10.1016/j.intimp.2022.109008

Cited by 8 publications

(5 citation statements)

References 34 publications

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“…MMP2 and TIMP2 gene polymorphisms were associated with CRC risk in multiple populations 73,74 . In line with our ndings, some studies showed the expression and protein levels of MMP2 and TIMP2 were lower in CRC and were associated with better overall survival in CRC patients, suggesting the clinical implication of MMP2 and TIMP2 as biomarkers for CRC diagnosis [75][76][77][78][79][80] . Experiment study also displayed the inhibition of TIMP2 in the invasion and migration of CRC cells in vitro and vivo 77 .…”

Section: Discussionsupporting

confidence: 84%

Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome

Sun

Zhao

Jiang

et al. 2022

Preprint

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Background:Proteome is a major source of therapeutic targets. We conducted a proteome-wide Mendelian randomization (MR) study to identify candidate protein markers and therapeutic targets for colorectal cancer (CRC). Methods: Protein quantitative trait loci (pQTL) were derived from seven published genome-wide association studies (GWAS) on plasma proteosome, and summary-level data were extracted for 4,853 circulating protein markers. Genetic associations with CRC were obtained from a large-scaled GWAS meta-analysis (16,871 cases and 26,328 controls), the FinnGen cohort (4,957 cases and 304,197 controls) and the UK Biobank (9,276 cases and 477,069 controls). Colocalization and summary-data-based MR (SMR) analyses were performed sequentially to verify the causal role of candidate proteins. Single cell-type expression analysis, protein-protein interaction (PPI), and druggability evaluation were further conducted to detect the specific cell type with enrichment expression and prioritize potential therapeutic targets. Results: Collectively, genetically predicted levels of 13 proteins were associated with CRC risk. Elevated levels of two proteins (GREM1, CHRDL2) and decreased levels of 11 proteins were associated with an increased risk of CRC, among which six (CLSTN3, POLR2F, ADPGK, CSAG1, STXBP6, FUT3) were novel protein markers. These protein-coding genes mainly expressed in tissue stem cells, epithelial cells, and monocytes in colon tumor tissue. Two interactive pairs of proteins (GREM1 and CHRDL2; MMP2 and TIMP2) were identified to be involved in osteoclast differentiation and tumorigenesis pathways; four proteins (POLR2F, CSF2RA, CD86, MMP2) have been targeted for drug development on autoimmune diseases and other cancers, with the potentials of being repurposed as therapeutic targets for CRC. Conclusion: This study identified several protein biomarkers to be associated with CRC risk and provided new insights into the etiology and promising targets for the development of screening biomarkers and therapeutic drugs for CRC.

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Section: Discussionsupporting

confidence: 84%

Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome

Sun

Zhao

Jiang

et al. 2022

Preprint

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“…On the other hand, our results show that TIMP-2 expression correlates positively with the infiltration of CD8+ T cells, Neutrophils, and DCs. Interestingly, in stomach adenocarcinoma and colon adenocarcinoma, we also report that TIMP-2 was positively correlated with CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells [70]. We also found that TIMP-3 expression levels positively correlate with CD8+ T-cell infiltrates.…”

Section: Discussionsupporting

confidence: 66%

Biological and Clinical Significance of TIMPs Expression in Breast Cancer: a Bioinformatic Analysis

Cayetano-Salazar¹,

Arizmendi-Izazaga²,

Nava-Tapia³

et al. 2023

Preprint

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Tissue inhibitors of metalloproteinases (TIMPs) are essential players during tumor progression in various types of cancer, including breast cancer. TIMPs regulate the activity of matrix metallo-proteinases (MMPs) at different levels. However, a dual role for TIMPs in breast carcinogenesis, either promoting or inhibiting tumor progression, has been observed. By a comprehensive bioin-formatics analysis using different databases, we report that of the four TIMPs, only TIMP-1 is overexpressed in tumor breast tissue. However, TIMP-2, TIMP-3, and especially TIMP-4 present lower levels in breast tumor tissue than in normal tissue. Interestingly, high levels of TIMP-1 are associated with shorter survival in breast cancer patients. In contrast, low TIMP-2, TIMP-3, and TIMP-4 levels are associated with poor survival. Function enrichment analysis showed that TIMP-3 has the highest interactions with its target proteins and a higher number of processes re-lated to mammary carcinogenesis. We found differential expression of TIMP-1 concerning TIMP-3 and TIMP-4 in breast cancer and normal tissue. TIMP-4 has a significant relationship with cancer staging, including tumor size, lymph node spread, and metastasis. The correlation between immune cell infiltrates and TIMP expression is of great importance as they provide in-formation on breast cancer diagnosis, prognosis, progression, and response to treatment.

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“…Several studies have identified specific pathways contributing to the development and metastasis of both gastric and colorectal cancers, providing deeper insights into the connections between gastrointestinal tumors ( 31 , 32 ). The association between premalignant gastric lesions and colorectal neoplasms also suggests the necessity of updating screening recommendations for high-risk patient subgroups.…”

Section: Discussionmentioning

confidence: 99%

Retrospective cohort study investigating association between precancerous gastric lesions and colorectal neoplasm risk

Pan,

Zhang,

Fang

et al. 2024

Front. Oncol.

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BackgroundColorectal cancer (CRC) is considered the most prevalent synchronous malignancy in patients with gastric cancer. This large retrospective study aims to clarify correlations between gastric histopathology stages and risks of specific colorectal neoplasms, to optimize screening and reduce preventable CRC.MethodsClinical data of 36,708 patients undergoing gastroscopy and colonoscopy from 2005-2022 were retrospectively analyzed. Correlations between gastric and colorectal histopathology were assessed by multivariate analysis. Outcomes of interest included non-adenomatous polyps (NAP), conventional adenomas (CAs), serrated polyps (SPs), and CRC. Statistical analysis used R version 4.0.4.ResultsOlder age (≥50 years) and Helicobacter pylori infection (HPI) were associated with increased risks of conventional adenomas (CAs), serrated polyps (SPs), non-adenomatous polyps (NAP), and colorectal cancer (CRC). Moderate to severe intestinal metaplasia specifically increased risks of NAP and CAs by 1.17-fold (95% CI 1.05-1.3) and 1.19-fold (95% CI 1.09-1.31), respectively. For CRC risk, low-grade intraepithelial neoplasia increased risk by 1.41-fold (95% CI 1.08-1.84), while high-grade intraepithelial neoplasia (OR 3.76, 95% CI 2.25-6.29) and gastric cancer (OR 4.81, 95% CI 3.25-7.09) showed strong associations. More advanced gastric pathology was correlated with progressively higher risks of CRC.ConclusionPrecancerous gastric conditions are associated with increased colorectal neoplasm risk. Our findings can inform screening guidelines to target high-risk subgroups, advancing colorectal cancer prevention and reducing disease burden.

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TIMP2 is associated with prognosis and immune infiltrates of gastric and colon cancer

Cited by 8 publications

References 34 publications

Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome

Identification of novel protein biomarkers and drug targets for colorectal cancer by integrating human plasma proteome with genome

Biological and Clinical Significance of TIMPs Expression in Breast Cancer: a Bioinformatic Analysis

Retrospective cohort study investigating association between precancerous gastric lesions and colorectal neoplasm risk

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