As mentioned above, CD9 is a member of tetraspanin superfamily proteins. It seems that research on CD9 has never stopped, and results have not been consistent. Some studies reported that CD9 could inhibit cancer cells metastasis and invasion via modulating the function of integrins, it could be regarded as a suppressors of metastasis in solid tumors (25–27). Some researchers hold the different view, they think that CD9 inhibits cancer progression by maintaining normal cell adhesion and motility in malignant mesothelioma (28). However, some people hold completely opposite views on the function of CD9. They think CD9 is not a favorable factor to the prognosis of the cancer patients. CD9 could bind to ATP-binding cassette and lead to chemo resistance in gastric cancer (17). CD9 could also cooperate with heparin-binding epidermal growth factor-like growth factor (HB-EGF) and promote the progress of human gastric cancer. Up to now, more and more functions of CD9 have been discovered, but its physiologic functions and related regulatory mechanisms are still not particularly clear.
The relationship between the expression of CD9 and the OS of the various malignant cancer patients is the key point of this meta-analysis. The pooled HR of OS was 1.14, which means the high level of CD9 indicates a worse prognosis. But it was not statistically significant (P = 0.664). The pooled HR of DFS/RFS was 0.67, the high expression of CD9 turned out to be a protective factor, although it was not statistically significant too. This phenomenon maybe caused by the different function of CD9. Recent studies have reported that CD9 expression was negatively correlated with the high prevalence of lymph node metastasis. CD9 was also involved in cell growth, adhesion and movement, and the change of CD9 expression may be related to tumor invasion and metastasis (29). CD9 could also act as a metastasis suppressor by neutralizing Aggrus-mediated platelet aggregation as Nakazawa Y reported (30). What’s more, the result of DFS/RFS analysis could not be persuasive enough because of the limited number of included researches.
Because of the high heterogeneity, we had to conduct subgroup analysis. The results suggested that high level of CD9 indicate poor prognosis in hematological tumor and digestive system tumor. On the other hand, CD9 could be favorable factor of the squamous cell cancer. As mentioned above, this phenomenon could be caused by different function of CD9. When it came to nationality, China was a risk factor for tumor prognosis. However, no significant effect was observed in ethnicities. This difference can be attributed to environmental differences.
We must admit there are still some restrictions that cannot be ignored in this meta-analysis. At first, there is no standard for the high level of CD9 expression. In some studies, more than 10% are considered positive (16), while in other studies the standard is 30% (31) or 50% (18), and because the method of determination is different, there must be some error between the research results and the real results. Secondly, the number of studies included in the analysis is still too small, especially for the DFS/RFS analysis, and may reduce the statistical power of the result. Thirdly, we had to calculate or extracted data from the survival curves because of the absence of some critical survival information, which would bring some minor differences to the conclusion. At last, these studies did not mention the survival data of MFS/PFS, so we could not conduct research about this aspect. These factors should be taken into account in drawing a conclusion.