We detected the expression levels of several biomarkers in CRC in previous exploratory studies and found that SHP2 may be associated with patient prognosis 16. To confirm the prognostic value of SHP2 in CRC, we investigated SHP2 expression levels in 860 CRC tumors and 197 tumor-adjacent normal tissues and analyzed the relationship between SHP2 expression levels and clinicopathological parameters. We found that SHP2 expression was significantly higher in CRC tissues than in adjacent noncancerous tissues. In the same case, SHP2 was moderately to strongly expressed in cancer tissue and negatively to weakly expressed in normal mucosa adjacent to the tumor. Although there are some missing data when collecting clinical data, we still found that the expression level of SHP2 is related to the depth of invasion, lymph node metastasis and TNM stage according to the existing data, suggesting that SHP2 is related to the invasion and metastasis of CRC. Survival curves using the Kaplan-Meier method revealed that CRC patients with higher SHP2 expression had better prognoses. Cox proportional hazards regression for univariate analysis showed that the expression level of SHP2 was a prognostic factor for CRC. Moreover, multivariate analysis indicated that SHP2 is an independent prognostic indicator of CRC. Therefore, SHP2 is considered a useful factor for predicting the prognosis of patients with CRC. However, our results did not show a correlation between SHP2 expression and distant metastasis, which requires further confirmation from multicenter clinical samples.
By observing the immunohistochemical staining, we found that SHP2 was expressed in a “none” or “all” manner except in tumors containing mucinous adenocarcinoma, which means that nearly all the tumor cells were stained in the SHP2 positive cases, while virtually no tumor cells were stained in SHP2 negative cases. In the same tumor, SHP2-positive cells exhibited a uniform staining intensity; therefore, we did not consider the percentage of positive cells in the immunohistochemical staining results.
SHP2 was expressed diffusely and uniformly in the cytoplasm and nucleus of tumor cells, whereas only the nucleus and perinuclear cytoplasm were stained in mucosal epithelial cells adjacent to the tumor, yet the regions near the luminal surface were not. The specificity of cell type may be another feature of SHP2 expression. SHP2 is always negatively expressed in mucinous cells, both in the normal mucosal epithelium and in mucinous adenocarcinoma. This phenomenon has not been previously reported in the literature; however, the reasons for this are still unknown.
SHP2 plays important physiological roles in organism development and homeostasis maintenance by regulating fundamental intracellular signaling pathways in response to a variety of growth factors and hormones 18. SHP2/ERK signaling plays an anti-infection role in colonic mucosal erosion and colitis 19. Furthermore, SHP2 expression levels are upregulated in many solid tumors. Our findings demonstrate that SHP2 is upregulated in colorectal cancer, which is similar to that reported in the literature on pancreatic ductal adenocarcinoma 13, gastric cancer 20 and oral cancer 21.
However, contrary results have been reported regarding the prognostic significance of SHP2 expression, which has been associated with poor prognosis 12, 20, 22. Thus, the prognostic effect of SHP2 may not be equivalent in different cancers; it is highly influenced by the tumor site 15. SHP2 may possibly play a duplicitous role in tumorigenesis 23. Even in the same type of cancer, SHP2 has been reported to play different roles as a suppressor in hepatocellular carcinogenesis 24 and as an enhancer in liver cancer progression 12.
Inhibitors of the tyrosine phosphatase SHP2 have been extensively studied for their broad roles in tumors 25. SHP2 is not only a useful predictor of prognosis, but is also a promising target for pro-senescence cancer therapies 26. SHP2 deletion reduces tumor microvascular density and leads to tumor vascular normalization, which is why SHP2 in endothelial tumors is a promising antiangiogenic target for cancer therapy 27. SHP2 plays an important role in regulating immune cell functions in the tumor microenvironment; therefore, SHP2 inhibitors may be a promising strategy for cancer immunotherapy 28. In addition, SHP2 inhibition has been shown to enhance responses to anti-PD-1 blockade, further suggesting the therapeutic effects of targeting SHP2 29.
Although great progress has been made in studies focusing on SHP2-related mechanisms, the specific processes of SHP2 involvement in the molecular mechanism remain unclear in CRC. Therefore, the molecular mechanism by which CRC patients with high SHP2 expression achieve longer survival warrants further study.