Shh Signaling Proteins Function as Independent Predictors and Contribute to Immune Infiltration in Kidney Renal Clear Cell Carcinoma

Background: Sonic hedgehog (SHH) signaling, originally identified as a key regulating pathway of embryonic development, has also been shown to be associated with various cancers. However, the role of SHH signaling in renal kidney clear cell carcinoma (KIRC) is still obscure. Method: TCGA data was used for analyzing roles of SHH signaling proteins in KIRC with the help of data mining websites and the R software. Findings: In the present study, we detected abnormal expression levels of SHH signaling proteins and examined their potential as independent predictors of prognosis in KIRC. We also explored possible functions of SHH pathway proteins in KIRC progression and immune infiltration. The results showed that KIF7, GLI1, GLI2, SUFU, and PTCH2 were overexpressed while SMO, PTCH1, and SHH were downregulated in KIRC. High expression levels of KIF7 and GLI2 were significantly correlated with a poor prognosis in KIRC. SHH signaling proteins were found to be highly conserved and could regulate epithelial-mesenchymal transition (EMT) and the cell cycle in KIRC. Furthermore, the expression of GLI2, PTCH2, and SUFU were correlated with the infiltration of CD4+ T cells. GLI family and PTCH family proteins were found to be associated with PD-1 signaling and natural killer cell functions, respectively. We also found out that among various types of cells in advanced renal cell carcinoma (RCC), SHH signaling genes were found to mainly expressed in fibroblasts. And it was shown that the expression of SHH pathway genes was positively correlated with myofibroblasts markers. The drug sensitivity analysis indicated that KIF7 was sensitive to docetaxel and bleomycin (50 μM). Interpretation: These results suggested that SHH signaling proteins play a key role in the progression and prognosis of KIRC, and KIF7 may represent a promising potential therapeutic target in KIRC. Funding: This study was supported, by the National Natural Science Foundation of China (grant nos. 82073264 and 81770228).Declaration of Interest: The authors declare that they have no conflicts of interest.