Abstract
Colorectal cancer (CRC) develops by genetic and epigenetic alterations. However, the molecular mechanisms underlying metastatic dissemination remain unclear and could benefit from multi-omics investigations of specific protein families. Matrix metalloproteinases (MMPs) are proteolytic enzymes involved in ECM remodeling and the processing of bioactive molecules. Increased MMP expression promotes the hallmarks of tumor progression, including angiogenesis, invasion, and metastasis, and is correlated with a shortened survival. Nevertheless, the collective role and the possible coordination of MMP members in CRC are poorly investigated. Here, we performed a multi-omics analysis of MMP expression in CRC using data mining and experimental investigations. Several databases were used to deeply mine different expressions between tumor and normal tissues, the genetic and epigenetic alterations, the prognostic value as well as the interrelationships with tumor immune-infiltrating cells (TIICs). A special focus was placed on to MMP2 and MMP9: their expression was correlated with immune markers and the interaction network of co-expressed genes disclosed their implication in epithelial to mesenchymal transition (EMT) and immune response. Finally, the activity levels of MMP2 and MMP9 in a cohort of colon cancer samples, including tissues and the corresponding sera, was also investigated by zymography. Our findings suggested that MMPs could have a high potency, as they are targeted in colon cancer, and might serve as novel biomarkers, especially for their involvement in the immune response. However, further studies are needed to explore the detailed biological functions and molecular mechanisms of MMPs in CRC, also in consideration of their expression and different regulation in several tissues.
Highlights
Colorectal cancer (CRC) represents the third most common type of cancer and the second most prevalent cause of cancer death, and its incidence is increasing [1]
We analyzed by data mining 24 Matrix metalloproteinases (MMPs) genes, grouped into six sub-families according to their substrate specificity (Table 1): (1) Collagenases: MMP1, MMP8, and MMP13; (2) Gelatinases: MMP2 and MMP9; (3) Stromelysins: MMP3, MMP10, and MMP11; (4) Matrilysins: MMP7 and MMP26; (5) Membrane-bound/associated MMPs: MMP14 to MMP17, MMP24, and MMP25; (6) Others MMPs: MMP12, MMP19 to MMP23, MMP27, and MMP28
14 of 24 MMP members were soundly deregulated (Table 2); among these, MMP1, MMP3, MMP7, MMP9, MMP10, MMP11, MMP12, MMP13, and MMP14 were significantly upregulated in tumor tissues, while MMP15, MMP17, MMP25, MMP27, and MMP28 were significantly downregulated in CRC compared with normal tissues
Summary
Colorectal cancer (CRC) represents the third most common type of cancer and the second most prevalent cause of cancer death, and its incidence is increasing [1]. Colorectal cancer develops from the accumulation of somatic genetic alterations. Fearon and Vogelstein proposed a multi-step model of carcinogenesis, in which accumulating mutations occur early during carcinogenesis; concurrently, additional mutations ensure the full transition to malignancy [2]. This pathway is called the chromosomal instability (CIN) pathway. Another pathway for CRC pathogenesis involves microsatellite instability [3] These genetic changes ensure the tumor’s anti-apoptotic, pro-angiogenic and proliferative properties, consequential to the altered expression of oncogenes, tumor suppressor genes, and/or microRNAs and non-coding RNAs, which contribute to tumor progression. The discovery of new biomarkers able to detect colon cancer at early stages and/or that can differentiate metastatic versus nonmetastatic cancers is necessary both for an accurate diagnosis and the development of new targeted therapies
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