High Matrix Metalloproteinase 28 Expression is Associated with Poor Prognosis in Pancreatic Adenocarcinoma

Na Liu; Liang Zhong; Guangcheng Ni; Jiao Lin; Liang Xie; Taiwen Li; Hongxia Dan; Qianming Chen

doi:10.2147/OTT.S309576

High Matrix Metalloproteinase 28 Expression is Associated with Poor Prognosis in Pancreatic Adenocarcinoma

Onco Targets Ther. 2021 Aug 10:14:4391-4406. doi: 10.2147/OTT.S309576. eCollection 2021.

Authors

Na Liu¹, Liang Zhong¹, Guangcheng Ni¹, Jiao Lin¹, Liang Xie¹, Taiwen Li¹, Hongxia Dan¹, Qianming Chen¹

Affiliation

¹ State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, People's Republic of China.

Abstract

Purpose: Pancreatic adenocarcinoma (PAAD) is a devastating disease with high mortality and morbidity. Matrix metalloproteinase 28 (MMP28) has been associated with carcinogenesis of many human cancers. However, little is known about the potential prognostic value and underlying regulatory mechanisms of MMP28 in PAAD.

Methods: The relationship between MMP28 expression level and various clinicopathological parameters was analyzed in TCGA-PAAD cohorts. MMP28-correlated genes in the TCGA-PAAD cohort were identified and enrichment analysis according to the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes was conducted using LinkedOmics. Protein-protein interaction and transcription factors-miRNA co-regulatory networks were constructed with the use of NetworkAnalyst. Then, the distribution of immune cells related to MMP28 expression in blood was analyzed using the Human Protein Atlas, and the tumor microenvironment of PAAD was analyzed by the TIMER 2.0 database. To investigate the biological function of MMP28 in PAAD, siRNA was constructed to knock down the MMP28 gene in vitro.

Results: High MMP28 expression is associated with poor overall survival and disease-free survival in PAAD patients. The expression of MMP28 in PAAD is most significantly correlated with KRT19, IL1RN, and ANXA2 genes. Network analysis revealed that MIR-181 family, TAFs, and CDC6 are potential regulators of MMP28. Furthermore, naive CD4⁺ T cell, naive CD8⁺ T cell, and mucosal-associated invariant T cell enrichment in blood were correlated with MMP28 expression. Furthermore, high MMP28 expression was correlated with a decrease in B cell, naive CD4⁺ T cell, naive CD8⁺ T cell, and endothelial cell presence in the tumor microenvironment in PAAD. Finally, genetic knockdown of MMP28 could restrain the proliferation, migration, and invasion of PAAD cells.

Conclusion: Our findings indicate that high MMP28 expression in PAAD is associated with cancer progression, invasion, and metastasis. Hence, MMP28 might serve as an independent prognostic biomarker and a prospective therapeutic target for PAAD.

Keywords: matrix metalloproteinase 28; metastasis; pancreatic adenocarcinoma; prognosis.

Grants and funding

This work was supported by the following Grants: National Natural Science Foundation of China (81572663, 82071125, 81972551, 81702701, 82071137, 81602375), the CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-004), 111 Project of MOE (B14038), China and the Sichuan Science and Technology Program (2020YJ0286).