Background
Colon cancer is the most frequent digestive system cancer in the world. It is also the third most common malignant tumor in the United States. In 2012, the estimated new cases of colon cancer were 103,170 throughout the country [
1]. With the development of economy and the changes in dietary patterns, the incidence of colon cancer is also increasing rapidly in China. Now, colon cancer is the fourth most common malignant tumor and the third leading cause of cancer death in Chinese people [
2].
The invasion and metastasis of cancer cells always result in treatment failure. Extracellular matrix (ECM) degradation is an important stage of tumor metastasis, which is regulated with matrix metalloproteinases (MMPs) [
3,
4]. The MMPs carry out the selective proteolytic degradation of ECM, which is an imperative step for the migration and invasion of tumor cells. MMPs are divided into six categories according to the specificity of their substrates as follow: interstitial collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs and others [
5]. MMP-9 is an important member of the gelatinases. It is also called gelatinase B or 92 kDa type IV collagenase [
6]. The gene of MMP-9 is located in 20q11.2-q13.1. MMP-9 can be involved in the development of several human malignancies, as degradation of collagen IV in the basement membrane and the extracellular matrix facilitates tumor progression, including invasion, metastasis, growth and angiogenesis [
7].
However, the correlation between MMP-9 expression and survival or prognosis in colon cancer is still inconclusive. Here, we immunohistochemically investigated 68 specimens of colon cancer tissues and corresponding distal normal mucosa tissues. Then, the association of MMP-9 expression with clinicopathologic features and prognosis was analyzed by univariate and multivariate analysis. The results of this study could provide new evidence for the research of MMP-9 in colon cancer.
Discussion
Colon cancer is one of the most familiar malignant neoplasmas. The pathogenesis of tumor is a process of multiple factors, multiple steps and many stages, which are concerned with the abnormalities of many oncogenes, tumor suppressor genes, mismatch repair genes and cellular adhesive factors [
10]. But the invasion and metastasis of tumor cells were main causes for cancer treatment failure among these factors. MMP-9 is the most complex member of the MMPs family in terms of domain structure. It is capable of degrading decorin, elastin, fibrillin, laminin, gelatin, and types IV, V, XI and XVI collagen [
11,
12]. The expression of MMP-9 was regulated by many upstream factors. Levels of phosphorylated signal transducer and activator of transcription 3(STAT3) regulated the MMP-9 gene in pediatric patients with ulcerative colitis [
13]. Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid distributed in medical herbs, also suppressed colon cancer cell migration by inhibiting MMP-9 expression [
14]. Increased CO
2 concentration also elevated the mRNA expression of MMP-9 and invasive capability in colon cancer cell lines and human samples derived from a peritoneal metastasis [
15]. Knockdown of metastasis-associated in colon cancer 1(MACC1) expression using shRNA reduced hepatocellular carcinoma Huh7 cell migration and invasion abilities, which were associated with the downregulation of MMP-9 protein [
16]. Detected by using a luciferase reporter construct and western blots, piwi-like protein 2 (Piwil2) may regulate a 2-kb MMP-9 promoter fragment and apoptotic pathways in colon cancer [
17].
Overexpression of MMP-9 has been found to associate with the invasion and metastasis of cancer [
18]. The level of MMP-9 expression showed a statistically significant correlation (
P < 0.001) with the disease histopathologic grade, stage, metastatic potential, recurrence potential, and survival in patients with squamous cell carcinoma of the larynx. The Kaplan-Meier curve linearly showed the MMP-9 expression as a predictor of survival to be significantly (
P < 0.001) associated with survival [
19].
The increased MMP-9 expression makes the main contribution to the invasive potential of squamous cell cervical carcinomas [
20]. Elevated serum MMP-9 correlated with distant metastasis and poor survival in patients with squamous cell carcinoma (SCC) over either the head and neck or the esophagus [
21]. Elevated serum MMP-9 level was also associated with reduced disease-free survival (DFS) of breast cancer [
22].
In this study, we found that MMP-9 expression in colon cancer tissues (47/68, 69.1%) was significantly higher than that in corresponding distal normal mucosa tissues (3/68, 4.4%), and there was a statistically significant difference (χ2 =64.602,
P <0.001) between them. Furthermore, high levels of MMP-9 expression in colon cancer cells correlated with lymph node metastasis and with Dukes’ stage. Therefore, these findings suggested that MMP-9 was likely to play a role in promoting tumor invasion and metastasis. Meanwhile, Kaplan-Meier analysis showed that the differences of survival in metastasis of lymph node groups, infiltrative depth groups, MMP-9 expression group and Dukes’ stage group were highly statistically significant. Cox multivariate analysis suggested that MMP-9 might serve as an independent marker for poor prognosis. Unsal D
et al. reported that MMP-9 expression was characterized by poor overall survival and DFS in patients with Stage II/III rectal carcinoma [
23]. Here, our results showed that MMP-9 might be correlated with the metastasis of lymph node, and its elevated expression might be an adverse prognostic indicator for the patients of colon cancer. Although the detailed molecular mechanism involved in this process is less well defined, this study still has potential clinical benefits. The MMP-9 expression that could be detected by immunohistochemistry may be a useful molecular marker to predict the prognosis in colon cancer patients.
Conclusions
In conclusion, our study suggests that MMP-9 plays an important role in invasion and metastasis of colon cancer, and thus becomes a useful indicator for clinical assessment of tumor biological behavior and prognosis in colon cancer patients.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
BY drafted the manuscript. JF and ZR designed the study and helped in drafting the manuscript. FT, BZ, and YZ collected the data and performed the statistical analysis. All authors have read and approved the final manuscript.