High expression of MMP19 is associated with poor prognosis in patients with colorectal cancer

Colorectal cancer (CRC) is the third most common and the third leading cause of cancer-related death in the United States [1]. In China, both the incidence and mortality rate of CRC has been increasing, and CRC is ranked as the third leading cause of cancer-related deaths [2]. The development of distant metastasis is the main reason of cancer-related death regardless of effective surgical procedures and systemic chemotherapy. Approximately 20–25% of patients are initially diagnosed with synchronous metastases, of which approximately 50% ultimately develop metachronous disease after colectomy [3, 4]. The survival outcome of CRC is mainly determined by tumor stage and some other clinicopathological factors. However, the heterogeneity of this disease makes it difficult to predict patient prognosis with these traditional factors [5]. Recent genetic and molecular analyses of CRC have identified a set of predictive biomarkers, including RAS status, BRAF mutation and mismatch repair protein expression, that can aid in the identification of patients who are at high risk of disease progression or recurrence [3, 6‐8]. Although available biomarkers are commonly used for predicting long-term outcome, some previous studies have reported that a proportion of patients are misdiagnosed [7, 8]. Therefore, the identification of novel markers that can be used to screen various prognostic risk subgroups to guide individual treatment is urgently needed.

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that involve in a variety of physiological processes [9], and they act in concert in tumor invasion and metastasis [10]. Over the years, they have been investigated for their roles in cancer progression and metastasis [9, 11‐14]. MMP14 plays an important role in CRC progression and prognosis [15]. Immunohistochemical score based on major members of MMP/TIMP profile can identify a distinct group of colorectal cancers with poor prognosis [14]. However, some MMPs, such as MMP19, have not been fully investigated in CRC. MMP19 was first isolated as an autoantigen from the synovium of a rheumatoid arthritis patient [16, 17]. MMP19 contains classical MMP structural domains, including a signal peptide, pro-peptide, catalytic domain, hinge region, and C-terminal domain [17, 18]. MMP19 is reportedly involved in the progression and metastases of various cancers, but its role in CRC remains unknown.

In this study, we used The Cancer Genome Atlas (TCGA) and whole-genome expression microarray (Gene Expression Omnibus, accession number GSE39582) databases to investigate the expression of MMP19 and RNA sequence. Furthermore, we explored the relationship between MMP19 expression and cancer prognosis using our data to determine whether MMP19 can serve as a valuable prognostic predictor in CRC patients.

With recent advances in high-throughput technologies (e.g., RNA deep sequencing), the transcriptomes of many tumors have been surveyed and many novel biomarkers and therapeutic targets have been identified. To validate MMP19 as a potential novel target gene to predict survival, we designed our study in three steps. First, we found MMP19 as a potential novel biomarker in terms of survival in the TCGA database. Second, we studied MMP19 in the GSE39582 database and confirmed it as novel biomarker for CRC. Finally, because some important clinical characteristics were missed in the TCGA and GSE39582 database, such as strategies of adjuvant therapy, and the quality of surgery,, we further validated the results from our own database. We found that MMP19 expression was significantly upregulated in cancer tissues relative to the normal controls, and that high MMP19 expression was associated with inferior clinical characteristics. Importantly, MMP19 was validated as an independent predictor for both OS and DFS for CRC after colectomy. Our results point to a crucial role for MMP19 in the evolution of CRC.

MMP19 is a classical member of the MMP family, which consists of at least 23 enzymes [17]. MMP19 shares the typical structural domains of MMP, including a signal peptide, propeptide, catalytic domain, hinge region, and C-terminal domain [18]. MMP19 has been gradually recognized as an important oncogene in carcinogenesis and progression. It is associated with increased mortality and promotes metastatic behavior in non-small cell lung cancer (NSCLC) [25]. An increase in MMP19 expression indicates the progression of cutaneous melanoma and might augment melanoma growth by promoting the invasion of tumor cells [26]. MMP19 is highly expressed in astroglial tumors and promotes the invasion of glioma cells [27]. For CRC, a previous study reported that MMP19 may involve in malignant transformation, is low expressed in normal mucosa, and is upregulate during neoplastic progression [28], but its prognostic value has not been reported. Here, we provide new evidence that MMP19 plays a crucial role in CRC. High MMP19 expression was significantly correlated with lymph node metastases and intramural vascular invasion, which suggests that MMP19 may play a critical role in CRC invasion and metastases. Distant metastases and recurrence are two main reasons for cancer-related death; thus, it was not surprising that high MMP19 expression was correlated with a poor prognosis in CRC. Similar, increased MMP19 gene expression correlates with a worse prognosis and facilitates invasion in NSCLC [25].

Although we obtained conclusions from three independent databases, there were some limitations in our study. First, we only investigated the clinical significance of MMP19 in CRC using patient samples; no in vitro study or animal models were used in this study. Second, a further study is needed to understand the mechanisms underlying the function of MMP19 in CRC progression.

In summary, our results demonstrate that MMP19 is upregulated in CRC and is a potential predictor of CRC, which provides additional information for predicting survival and developing a therapeutic strategy. Our results warrant further studies on the detailed mechanisms by which MMP19 facilitates tumor progression in CRC.