Prognostic and Therapeutic Potential of the OIP5 Network in Papillary Renal Cell Carcinoma

SIMPLE SUMMARY: Papillary renal cell carcinoma (pRCC) is an aggressive kidney cancer. Currently, there are no effective prognostic biomarkers and lack of efficacious therapies in treating pRCC. We report a novel and critical pRCC oncogenic factor OIP5. Its expression is increased in pRCC and the upregulation is associated with adverse features. High levels of OIP5 effectively predict pRCC recurrence and fatality. OIP5 promotes pRCC cell proliferation and tumor formation through complex processes. A 66-gene multigene panel (Overlap66) was constructed. Overlap66 is novel and robustly predicts pRCC recurrence and fatality. High risk pRCCs stratified by Overlap66 are associated with immune suppression. Furthermore, PLK1 is a component gene of Overlap66; PLK1 inhibitor significantly reduced OIP5-promoted pRCC cell proliferation in vitro and tumor growth in vivo. Collectively, Overlap66 can effectively stratifies high-risk pRCCs and these tumors can be treated with PLK1 inhibitors. Our findings can be explored for personalized therapy in pRCC patients. ABSTRACT: Papillary renal cell carcinoma (pRCC) is an aggressive but minor type of RCC. The current understanding and management of pRCC remain poor. We report here OIP5 being a novel oncogenic factor and possessing robust prognostic values and therapeutic potential. OIP5 upregulation is observed in pRCC. The upregulation is associated with pRCC adverse features (T1P < T2P < CIMP, Stage1 + 2 < Stage 3 < Stage 4, and N0 < N1) and effectively stratifies the fatality risk. OIP5 promotes ACHN pRCC cell proliferation and xenograft formation; the latter is correlated with network alterations related to immune regulation, metabolism, and hypoxia. A set of differentially expressed genes (DEFs) was derived from ACHN OIP5 xenografts and primary pRCCs (n = 282) contingent to OIP5 upregulation; both DEG sets share 66 overlap genes. Overlap66 effectively predicts overall survival (p < 2 [Formula: see text] 10(−16)) and relapse (p < 2 [Formula: see text] 10(−16)) possibilities. High-risk tumors stratified by Overlap66 risk score possess an immune suppressive environment, evident by elevations in Treg cells and PD1 in CD8 T cells. Upregulation of PLK1 occurs in both xenografts and primary pRCC tumors with OIP5 elevations. PLK1 displays a synthetic lethality relationship with OIP5. PLK1 inhibitor BI2356 inhibits the growth of xenografts formed by ACHN OIP5 cells. Collectively, the OIP5 network can be explored for personalized therapies in management of pRCC patients.