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

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.

Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion

“…First, we profiled the expression status of 411 gene transcripts associated with the ECM and cell adhesion (QIAGEN). WT and PKN2 KO PSCs were cultured in complete medium or exposed to TGF-β1 for 72 h. PKN2 deletion predominantly resulted in the upregulation of ECM-associated genes under 2D cell culture conditions ( Figures 2 A and 2B), including genes associated with metastasis (Serpine2, Fmod, Itgbl1, Aspn, MMP28, and Col6a3; Buchholz et al., 2003 ; Liu et al., 2021 ; Wiechec et al., 2021 ). Many of these genes were also differentially expressed (DE) in PKN2 KO PSCs compared with WT PSCs following TGF-β1 stimulation ( Figures 2 B and 2C; Table S1 ).…”

PANoptosis-related molecular subtype and prognostic model associated with the immune microenvironment and individualized therapy in pancreatic cancer

“…TIME, including innate and adaptive immune cells, extracellular immune factors, and molecules on the cell surface, are critically involved in tumorigenesis (53)(54)(55). Studies have that macrophages, DCs, neutrophils, myeloid suppressor cells, NK cells, innate lymphocytes, and cytokines in TME could interfere with immune function, inhibit anti-tumor immune response mediated by T cells, stimulate angiogenesis, and promote the proliferative, invasive and metastatic ability of cancer cells (56)(57)(58)(59). Our results showed a significant increase in macrophages, resting and activated DCs, as well as activated mast cell infiltration in patients in PANcluster A.…”

Molecular characterization of matrix metalloproteinase gene family across primates

“…MMPs comprise a family of zinc-dependent endoproteinase, responsible for degrading extracellular matrix components [ 1 ]. Deregulation of the MMPs has been implicated in many aging-related diseases, such as Alzheimer’s disease, Parkinson's disease, age-related macular degeneration, bone diseases and cancers [ 6 , 9 , 11 – 13 , 15 – 18 ]. Although biochemical properties of MMPs has been intensively studied, accumulated evidences have shown that our understanding of the MMPs is far from absolute, and some discoveries even have conflicted conclusions with previous findings [ 23 , 40 ].…”

“…Cancers, occurring mostly in middle age and above, have been linked to MMPs with evidence as they are an important factor promoting tumor progression [ 14 ]. This is especially true for tumors like pancreatic adenocarcinoma, prostate adenocarcinoma, bladder urothelial carcinoma and melanoma, which are commonly at risk above the age of 50 [ 15 – 18 ]. Collectively they reveal that MMPs widely participate in physiological and pathological processes, and thus are promising targets for diagnosis and drug development of aging-related diseases.…”