Abstract
Skin cutaneous melanoma (SKCM) is the most lethal tumor among three of the major malignant cancers of the skin. The mechanism underlying the malignant biological behaviors of SKCM is not fully clear. Our study intended to verify the molecular mechanism of proteasome 26 S subunit ATPase 2 (PSMC2) in malignant biological behaviors of SKCM. The Cancer Genome Atlas (TCGA) database was used to analyze the expression of PSMC2 in SKCM and its impact on prognosis. PSMC2 expression in 105 paired SKCM tissues was investigated by immunohistochemistry (IHC), its functional roles were verified using a series of cell experiments, and the underlying pathway was detected by protein-chip technology and gene set enrichment analysis. We found that PSMC2 was significantly upregulated in SKCN patients from TCGA datasets and verified in clinical SKCM tissues. Moreover, high PSMC2 was shown to closely correlate with the pathological stages and lymphatic metastasis of SKCM patients. Functionally, knockdown of PSMC2 suppressed the progression of SKCM through inhibiting cell proliferation, migration, and DNA damage in vitro as well as cell growth in vivo, whereas inducing apoptosis, cycle arrest in G2 phase. Similarly, pharmaceutical inhibition of proteasome with MG132 mimicked the PSMC2 knockdown induced defects in cell cycle arrest, apoptosis and proliferation, while overexpression of PSMC2 has the opposite effects. Mechanistically, the silence of PSMC2 remarkably elevated the pro-apoptotic proteins DR6, IGFBP-4, p21, and p53, while inhibited the anti-apoptosis protein TRAILR-3 and the proteins related to the Wnt signaling pathway. The present study revealed that PSMC2 participated in a positive regulation to promote the progression of SKCM through regulating the Wnt signaling pathway. Our findings may offer a new mechanism underlying the development and progression of SKCM, and a deeper understanding of PSMC2 may contribute to SKCM treatment.
Highlights
Cutaneous melanoma (CM) is a common skin malignant tumor with a high fatality rate, degree of malignancy, rapid progress, strong invasiveness, and poor prognosis [1]
A high level of PSMC2 was closely associated with clinical characteristics of patients with Skin cutaneous melanoma (SKCM) To determine the expression of PSMC2 in SKCM, we first analyzed the mRNA expression profiles and the associated clinical characteristics in 461 cases of SKCM samples compared to 558 normal samples from The Cancer Genome Atlas (TCGA) dataset
A striking upregulation of PSMC2 were observed in SKCM samples (Fig. 1A, P < 0.05) from TCGA, which might imply an oncogenic role of PSMC2 in the development of SKCM
Summary
Cutaneous melanoma (CM) is a common skin malignant tumor with a high fatality rate, degree of malignancy, rapid progress, strong invasiveness, and poor prognosis [1]. Epidemiological studies show that the incidence of SKCM is gradually increasing with more than 20,000 new cases of SKCM every year and is one of the more rapidly improving incidence rates among malignant tumors in China [2]. The 5-year survival rate of SKCM is as high as 90% in the early stage (I, II) when there are no specific clinical manifestations, but most SKCM patients diagnosed is an advanced stage when the 5-year survival rate is less than 10% [4, 5]. Great progress was recorded in both the understanding of SKCM biology and genetics and biological immunization therapies of early diagnosis and prevention, this malignancy became a burden on health care worldwide due to its increasing incidence and the lack of effective advanced treatment [6]. It is essential to explore the pathogenesis and seek new therapy for patients with SKCM
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