WW domain-containing E3 ubiquitin protein ligase 1 depletion evokes antitumor effect in cutaneous squamous cell carcinoma by inhibiting signal transducer and activator of transcription 3 signaling pathway

Abstract

ObjectivesWW domain-containing E3 ubiquitin protein ligase 1 (WWP1) has been implicated in tumor progression. We aimed to investigate the role of WWP1 in cutaneous squamous cell carcinoma (CSCC).MethodsWWP1 gene and protein levels were detected using semi-quantitative reverse transcription-polymerase chain reaction, immunohistochemistry and western blotting. The effects of WWP1 on cell cycle, apoptosis, cell migration and invasion were examined by flow cytometry, wound healing and Transwell assays, respectively. The antitumor efficacy of WWP1 small interfering RNA was determined in CSCC tumor xenografts in mice.ResultsWWP1 expression was significantly higher in CSCC tissues and cells than in normal skin and cells, respectively. WWP1 expression was significantly associated with histological grade, invasion depth and lymph node metastasis in patients with CSCC. High expression predicted metastatic potential and an unfavorable prognosis. WWP1 downregulation suppressed tumor growth in vitro and in vivo, reduced cell migration and invasion, arrested the cell cycle in G0/G1 and induced apoptosis in A431 cells. WWP1 depletion also decreased phosphorylated signal transducer and activator of transcription 3 (STAT3), matrix metalloproteinase-2, cyclin D1 and Bcl-2, but did not affect total STAT3.ConclusionsWWP1 is a potential target for the diagnosis, prognosis and therapy of patients with CSCC.

The Impact of the Ubiquitin System in the Pathogenesis of Squamous Cell Carcinomas

“…Similarly to what was observed in other tumor contexts, WWP1 likely acts as an oncogene also in SCCs and elevated levels of WWP1 has been reported in HNSCC tissues and in several oral cancer cell lines [45]. Consistently, WWP1 depletion in cutaneous SCCs and HNSCC cells decreases tumor cell proliferation [46]. Although these data confirm the general view of WWP1 as a positive regulator of tumorigenesis, further in vivo evidence is required to assess its contribution during squamous carcinogenesis as well as to uncover the molecular mechanisms underlying its oncogenic function in SCCs.…”

WWP1 E3 ligase at the crossroads of health and disease

“…Studies suggest that WWP1 promotes cell growth and proliferation in various cancer types (Fig. 5A), including breast cancer [41,[106][107][108], prostate cancer [40], hepatocellular carcinoma (HCC) [109,110], oral cancer [111], gastric cancer [110,112], colorectal cancer (CRC) [113,114], osteosarcoma [115], papillary thyroid carcinoma (PTC) [116], cutaneous squamous cell carcinoma (CSCC) [117], intrahepatic cholangiocarcinoma (ICC) [118] and AML [119]. RNAi-mediated WWP1 depletion results in cell cycle arrest at G0/G1 or G2/M phase in HCC, osteosarcoma, CSCC, and AML, suggesting that WWP1 can enhance cell proliferation by accelerating cell cycle progression [110,115,117,119].…”

“…RNAi-mediated knockdown of WWP1 induces apoptosis in oral cancer [111], HCC [109,135], breast cancer [133], osteosarcoma [115], gastric cancer [112], cutaneous squamous cell carcinoma cells [117] and AML [119]. WWP1 inhibits apoptosis by promoting cleaved caspase3 and p53 expression in HCC [109].…”

“…Local invasion, migration, and distant metastasis enable cancer cells to spread into neighboring tissues, thus exacerbating cancer aggressiveness. RNAi and overexpression studies indicate that WWP1 facilitates migration and invasion in HCC [135], prostate cancer [137], breast cancer [138], CRC [113,114], PTC [116], gastric cancer [139], LSCC [140], osteosarcoma [115], CSCC [117]. In breast cancer, WWP1 negatively regulates CXCL12-induced CXCR4 lysosomal degradation, thereby facilitating breast cancer cell migration and bone metastasis, leading to poor prognosis (Fig.…”

“…5C3, [115]). Additionally, WWP1 enhances CSCC migration and invasion by reducing BCL2, Cyclin D1, pSTAT3, and Matrix Metalloproteinase-2 [117]. Hence, WWP1 might represent a promising therapeutic target for these cancers.…”