Previous studies have explored the relationship between PROX1 expression and clinicopathological parameters and prognosis in various cancers. Currently, a growing number of studies investigate the relationship between the expression of PROX1 and GC. PROX1 could be a biomarker to diagnose the GC is seriously inconsistent. Our meta-analysis showed the following: (I) the expression of PROX1 has no relationship with clinicopathological parameters of GC, (II) the expression of PROX1 has no relationship with overall survival and (III) the expression of PROX1 cannot be used as a biomarker for diagnosing and preventing GC.
Some studies reported there are no relations between the expression of PROX1 and clinicopathological parameters in GC patients (11–12). Several studies indicated the correlation between the expression of PROX1 and depth of invasion, cancer stage and lymph node metastasis. But the results were controversial. Kang-Jin Park et al. reported a total of 327 patients finding that PROX1 expression was associated with lymph node metastases and cancer stage in a positive manner but no relation with the depth of invasion (15). They discovered that overexpression of PROX1 increased lymphatic endothelial cell invasion and tube formation by increasing VEGF-C and VEGF-D expression, which may result in tumor lymphangiogenesis. MiR-489 was shown to suppress the formation of GC through the HDAC7 and P13k/AKT pathways, was a direct target of PROX1, and showed a negative association with PROX1 protein expression (14) (23). However, Laitinen A et al. reported 273 patients in total to indicate the expression of PROX1 is negatively correlated with the depth of invasion, lymph node metastasis and cancer stage by their study (10). They also think that the mechanism research in the relationship between PROX1 expression and the presence of GC in patients is not comprehensive yet. In our meta-analysis, PROX1 expression was not related with gender, TNM stage, depth of invasion, tumor size, stage, tumor cell metastasis, or lymph node metastasis in GC patients.
Many studies have revealed the relationship between PROX1 expression and prognosis of tumor patients but the role is controversial. Several studies support the correlation between high expression of PROX1 and shorter OS in GC patients (15–16). But the other studies reported a total of 598 patients finding that PROX1 overexpression is associated with a longer OS (11–13). However, our meta-analysis reveals that PROX1 expression is not related with OS at 1, 3, or 5 years. A comprehensive genomics-based bioinformatic analysis study that including 375 cases with OS data for GC patients also supports our viewpoint, confirmed that expression of PROX1 was not associated with OS at 1, 3 or 5 years.
PROX1, a reliable and sensitive marker for endothelial lymph cells, is also a specific marker for the development of some organs in the early stage (17–19). Previous studies have shown that PROX1 acts as a tumor promoter in gastrointestinal cancer cells, suggesting that it may be a potential prognostic biomarker and a novel target for GC treatment. (16). According to Abeer M. Hafez et al. (13) and KOJI UETA et al. (16), PROX1 expression acts as a good prognostic predictor for GC patients. But Ueta K et al. reported that PROX1 may be a bad promising prognostic biomarker (9). Our result in a comprehensive meta-analysis found that expression of PROX1 was not correlated with any clinicopathological parameters and OS at one, three and five years so it fails to be a meaningful biomarker to prevent and diagnose the GC.
This meta-analysis also has its limitations. First, the included studies were published only in English and Chinese. Second, the number of included studies and the total number of patients are small. Additional laboratory studies and analysis on larger, well-defined patient cohorts are required to untangle the connection between PROX1 and GC. Third, the extraction cutoffs (positive/negative or high/low) of the expression of PROX1 in GC tissues are not totally same and the standard of PROX1 expression is subjective. In addition, some data are derived from estimates of survival curves, not individual patient data. These may induce the heterogeneity or bias in our results. We will go on in-depth research when more studies about the relationship between PROX1 and GC in clinical parameters and OS emerge.