Skp2 expression has different clinicopathological and prognostic implications in lung adenocarcinoma and squamous cell carcinoma

Abstract

High expression of S-phase kinase associated protein 2 (Skp2) is associated with numerous clinicopathological parameters, including histology, lymph node metastasis, smoking status, differentiation and Tumor-Node-Metastasis stage in non-small cell lung cancer (NSCLC). Skp2 protein is overexpressed in lung squamous cell carcinoma (LUSC), compared with lung adenocarcinoma (LUAD), whilst the clinicopathological and prognostic implications in LUAD or LUSC remain unclear. A larger study is required to assess the differences in Skp2 expression between these NSCLC types. In the present study, the clinicopathological features and immunohistochemical expression of the Skp2 protein were studied in 500 patients with NSCLC (351 with LUAD and 149 with LUSC). Survival analyses were performed using Kaplan-Meier method and Cox regression model. Skp2 associated genes were identified based on the data from The Cancer Genome Atlas database. Skp2 was overexpressed in patients with LUSC, compared with LUAD (P<0.001). In histology subgroup analysis, differences in Skp2 protein expression were observed in patients with LUAD, based on sex, differentiation, smoking history, stage, lymph node metastasis and tumor diameter (P<0.05), but not in patients with LUSC except for smoking status. High Skp2 protein expression in patients with LUAD was associated with reduced overall survival (OS; P<0.001), but not in patients with LUSC (P=0.686). The multivariate analysis demonstrated that Skp2 expression is an independent unfavorable prognostic factor for OS in patients with LUAD (RR=1.845, P<0.05). Bioinformatics analyses revealed that minichromosome maintenance complex component 2, cell division cycle 45, replication factor C subunit 4, which are differently expressed in LUAD and LUSC, are associated with Skp2 expression and participate in DNA replication and G1/S transition. Skp2 protein expression differs in LUAD and LUSC. The clinicopathological and prognostic implications based on Skp2 expression in LUAD and LUSC should be considered different. LUSC with high Skp2 expression may have robust proliferation ability.

Prediction of Lymph-Node Metastasis in Cancers Using Differentially Expressed mRNA and Non-coding RNA Signatures

“…Therefore, our strategy ensured a complete representation of main cancer types defined by their anatomic tissues or original organs. Among the cancers, lung-derived adenocarcinomas and squamous cell carcinoma were both presented due to their high lymph-node metastasis risk in clinical cases (Zhong et al, 2018 ; Deng et al, 2019 ). For the following classifier establishment, a total of 2,491 mRNA samples, 2,364 miRNA samples, and 2,491 lncRNA samples were respectively selected, wherein normal, lymph-node metastatic, and non-metastatic cases were separated for each cancer type and cancer-specific profiles ( Table 1 ).…”

The Impact of [C16Pyr][Amp] on the Aggressiveness in Breast and Prostate Cancer Cell Lines

“…Indeed, MCM2 has been proposed to be an alternative proliferation marker to ki67 in the BrCa model [ 83 ]. Both MCM2 and SKP2 are implicated in the G 1 /S phase transition of the mitotic cell cycle and are reported to be co-expressed in lung and squamous cell carcinoma tissue samples [ 84 ], showing the close relationship between these two proteins. SKP2 is an oncogene that encodes a protein that regulates cell cycle entry and G 1 /S transition through a negative feedback loop targeting p21 and p27 degradation, thereby inhibiting cyclin-dependent kinases [ 85 , 86 ].…”

PPARG Could Work as a Valid Therapeutic Strategy for the Treatment of Lung Squamous Cell Carcinoma

“…Specifically, PPARG counter-regulated 12 molecules that were upregulated or downregulated by LSCC ( Figure 2). The expression levels of eight LSCC markers (XIAP, UBE2D1, SKP2, ACKR3, MI21, HOXA10, STAT1, and PDPN) were significantly upregulated in LSCC patients [13][14][15][16][17][18][19][20] and were downregulated by PPARG [21][22][23][24][25][26][27][28]. On the other hand, PPARG could activate multiple genes [29][30][31][32][33] inhibited by LSCC [34][35][36][37][38], including MIR 223, PTEN, ANGPT1, CYP2A6, and FOXA2.…”

“…In the LSCC diagnostic network (Figure 2), E2 ubiquitin-conjugating enzymes (UBE2D1), E3 ubiquitin ligases (XIAP), and SKP2 were involved in the regulation of protein ubiquitination. The expression of XIAP, UBE2D1, and SKP2 downregulated by PPARG at the transcriptional level [21,22,41] were [13][14][15]. PPARG may also play a role in the progression of LSCC by interfering upstream regulators of LSCC, as shown in Figure 3.…”