SHCBP1 regulates STAT3/c-Myc signaling activation to promote tumor progression in penile cancer.

A challenge in developing novel strategies for penile cancer (PC) is the limited understanding of the regulatory mechanisms involved in PC development. This study aims to examine the expression of SHC SH2 Domain-Binding Protein 1 (SHCBP1) in PC and to explore its oncogenic function. Aberrant SHCBP1 expression was observed in PC tissues compared with normal penile tissues. SHCBP1 expression was significantly associated with the pathological grade, T stage, nodal status, and pelvic lymph node metastasis, and could serve as an independent factor for unfavorable overall survival in PC. Manipulation of SHCBP1 expression affected cell proliferation, soft agar clonogenesis, and cell migration and invasion in PC cell lines. Moreover, we identified STAT3/c-Myc signaling as a potential downstream target of SHCBP1. SHCBP1 interacted with JAK2 and STAT3 upon EGF stimulation, which might regulate STAT3/c-Myc signaling activation in PC cells. Disruption of STAT3/c-Myc signaling attenuated cell proliferation and cell migration/invasion in PC cell lines. Nevertheless, overexpression of constitutively activated STAT3 or c-Myc rescued cell proliferation and cell migration/invasion caused by SHCBP1 depletion in PC cell lines. Consistently, SHCBP1 depletion attenuated STAT3/c-Myc signaling and suppressed tumor growth in a murine xenograft model. Importantly, correlated expression of SHCBP1, p-STAT3, and c-Myc was observed in PC tissues, confirming the clinical relevance of SHCBP1/STAT3/c-Myc signaling in PC. In conclusion, aberrant SHCBP1 expression could serve as a potential prognostic biomarker for PC. SHCBP1 might activate the STAT3/c-Myc signaling pathway to promote tumor progression in PC, which may serve as a potential target for PC treatment.