Lung cancer is the most common cause of cancer death worldwide . Molecular targeted therapy has shown significant effects on the treatment of tumor cells with somatic-driven oncogene, such as EGFR gene mutations, receptor tyrosine kinase gene (RET) and c-ros proto-oncogene (ROS) rearrangements . So, identification of the abnormal proteins in lung cancer may be of great value in the developing of lung cancer novel diagnostic and therapeutic methods . There is substantial evidence that MMP2 plays a major role in tumor cell-mediated degradation of extracellular matrix and its expression is closely related to the invasion, metastasis and prognosis of human malignant tumors [8–10, 14]. In this study, by measuring the serum level of MMP2 in patients with lung cancer, we explored the relationship between the MMP2 and the biological behavior of lung cancer invasion and metastasis.
In tissues level, we found that the MMP2 was highly expressed in lung cancer tissues but not in adjacent normal tissues, which suggested that high expression of MMP2 might potentially promote lung cancer occurrence and development. Previous studies have demonstrated that MMP2 is highly expressed in lung cancer tissues and lowly expressed in normal tissues [23, 24]. It is well known that the degree of differentiation of lung cancer cells is an independent factor affecting the prognosis of lung cancer patients, which is mainly based on that poorly differentiated lung cancer cells have a high degree of malignancy, and will soon be transferred and relapsed. In our study, we found that MMP2 was highly expressed in poorly differentiated lung cancer tissues, indicating that the high expression of MMP2 is associated with the malignant degree of lung cancer. Moreover, we found that the increased MMP2 in lung cancer tissues correlated significantly with lymph node metastasis and advanced TNM stage. In the analysis of the correlation between tumor size and MMP2 expression, we also noticed that with the increase of tumor volume, the expression of MMP2 showed an increasing trend. These results will show a clear suggestion that determining the expression of MMP2 is a valuable strategy for predicting the metastatic potential and prognosis of lung cancer. Previous studies have suggested that the MMP2 is associated with the molecular classification of some malignant tumors and has a close relationship with invasiveness, proliferation, lymphatic metastasis, and poor prognosis [9–11, 14], and our findings are similar to this.
Importantly, our study also showed that serum level of MMP2 in lung cancer patients significantly higher than that in benign lung disease group and healthy control group, thus suggesting a possible mechanism that MMP2 may be released from lung cancer cells to help the progress and spread of cancer cells. Some researches have showed that MMP2 secretion is increased during tumor formation and progression, so the amount of MMP2 in the blood circulation is detected by peripheral blood has been reported [25, 26]. TNM stage correlates with the prognosis of cancer patients, which is mainly based on lymph node metastasis, tumor size, and distant metastasis. Our study showed that increased serum MMP2 significantly correlated with the malignant features of lung cancer such as tumor size, invasion and metastasis of lymph nodes, low differentiation and advanced stage. The possible mechanisms for MMP2 to promote tumor progression is that MMP2 not only degrades the basement membrane and matrix to break through the matrix barrier, which promotes tumor invasion and metastasis, but also accelerate tumor growth and proliferation through neovascularization . Our findings suggested that the release of MMP2 was significantly increased in the tumorigenesis of lung cancer, suggesting that serum MMP2 could be used as a diagnostic and prognostic indicator of lung cancer.
Through the COX regression analysis, we found that lung cancer patients with over-expression of MMP2 had a shorter survival time compared with those without MMP2 over-expression. In addition, we also found that advanced TNM stage certainly was to be a strong risk factor for shorter survival time of lung cancer patients, with a hazard ratio value of 2.01. In our study, these two factors were implicated into the regression equation and the regression equation was as H(t)=[h0(t)] e (2.01 X8 + 1.49X9), which suggested that determining the expression of MMP2 in lung cancer tissues is helpful for predicting the prognosis of lung cancer patients. Previous study shows that the high expression of MMP2 in NSCLC was associated with tumor type and clinical stage and has a predictive value for low survival rates, short overall survival (OS) and disease free survival (DFS), suggesting that the use of MMP2 is valuable in determining the patients with more aggressive disease . We also analyzed the diagnostic value of serum MMP2 in patients with lung cancer. When we used serum MMP2 as an indicator to distinguish lung cancer from benign lung disease, it showed a better sensitivity of 96.51% and a considerable specificity of 65.85%. Previous studies show that tumor cells can secrete a variety of tumor-related proteins that help them proliferate and migrate [2–4, 22]. Increased MMP2 immunostaining and MMP2 serum level correlate with advanced tumor stage and the presence of distant metastasis, and serum MMP2 level may be a valuable prognosis variable and could help to stratify lung cancer patients into low- and high-risk groups . Our findings implied that serum MMP2 level could reflect the situation of progression and migration of lung cancer to a certain extent, which indicated that MMP2 could be a useful diagnostic, prognostic, and predictive biomarker of lung cancer.
A previous study suggests that the expression of MMP2 in tissues is closely related to lung adenocarcinoma, tumor recurrence, OS and DFS , however, another study suggests that MMP2 protein has nothing to do with the histology of NSCLC, but its mRNA level correlates with poorly differentiated tissue, distant metastasis and small cell lung cancer . These results indicate that the expression of MMP2 in NSCLC remains controversial yet. In addition to the findings of the above studies, we found that whether in tissues or in serum, MMP2 expression was associated with lymph node metastasis and tumor size and TNM stage. Based on the above results, we can think that MMP2 is associated with the occurrence and development of NSCLC, but the relationship between the two is still unclear. In the future, more multi-center, large-scale studies are still needed to solve this problem. More importantly, the intrinsic mechanism of MMP2 affecting the development of NSCLC remains unclear. However, There are opinions that MMP2 suppression decreases the expression of hypoxia inducible factor-1alpha (HIF-1alpha) and disrupts phosphoinosmde-3-kinase (PI3K) dependent vascular endothelial growth factor (VEGF) expression, and A549 xenograft tissue sections from mice that treated with MMP-2 small interfering RNA shows reduced expressions of VEGF, providing new insights into the mechanisms underlying MMP2-mediated VEGF expression in lung tumor angiogenesis . Another new study suggests that silibinin inhibits the MMP2 signaling pathway, and inhibits the proliferation, migration, and invasion of triple-negative breast cancer cells .
There are still some shortcomings in this study. Firstly, most patients of the surgical resection belong to patients with clinical stage IIIB and before, which may leads to a selective bias of the specimen. Secondly, the number of patients included is relatively small. Thirdly, this study did not concern the specific mechanisms by which MMP2 affects the growth, proliferation and metastasis of lung cancer cells. Hence, further experiments involving the mutual regulation-mechanism of MMP2 in lung cancer cells should be done. Fourthly, the study was a retrospective study, so used two independent patient groups to detect the MMP2 expression in lung cancer tissues and serum, which may weaken the strength of the evidence. In the future, further studies need to be performed to prove our conclusion more effectively through the method of detecting both expression levels of the tissue and the serum of MMP2 in the same patient.