ABSTRACT
The expression of calpain small subunit 1 (Capn4) is correlated with the invasion of several types of tumors. However, the roles of Capn4 in non-small cell lung cancer (NSCLC) remain unclear. In this study, we found that the expression of Capn4 in NSCLC tissues was much higher than that in nontumorous samples. High levels of Capn4 expression were associated with lymph node metastasis and large tumor size in NSCLC patients. The 5-year overall survival rate in the Capn4(high) group was significantly lower than that in the Capn4(low) group. In multivariate analysis, Capn4 was identified as an independent prognostic factor for overall survival. Moreover, in an in vitro analysis, downregulation of Capn4 expression by siRNA suppressed the invasive potential of lung cancer cells. Finally, we demonstrated that Capn4 enhanced the invasion ability of lung cancer cells by upregulating the expression of matrix metalloproteinase 2. Our findings indicated that Capn4 may represent a potential therapeutic target and a novel prognostic marker of NSCLC.
Subject(s)
Calpain/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Matrix Metalloproteinase 2/metabolism , Aged , Calpain/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Cell Line, Tumor , Female , Gene Knockdown Techniques , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , Lymphatic Metastasis , Male , Middle Aged , Prognosis , Up-RegulationABSTRACT
In non-small cell lung cancer (NSCLC), both USP7 expression and p53 gene status were reported to be an indicator of poor prognosis in adenocarcinoma patients; however, its roles and mechanisms in lung squamous cell carcinoma and large cell carcinoma need to be clarified. The USP7 expression was examined in NSCLC tumors (excluding adenocarcinoma), their corresponding non-tumorous tissues, and NSCLC cells. Then, the prognostic role of USP7 was analyzed in 110 NSCLC samples (excluding the adenocarcinoma). Finally, the roles and mechanisms of USP7 in the proliferation, metastasis, and invasion of a NSCLC cell were assessed using a specific vshRNA. The USP7 expression was higher in NSCLC tissues compared to non-tumorous samples, accordingly, the high level of USP7 was detected in NSCLC cell lines compared with HBE cell. After the USP7 downregulation, the H460 cells exhibited decreased metastasis/invasion in vitro and in vivo. The preliminary mechanism study indicated overexpression of USP7 might regulate the p53-MDM2 pathway by inducing the MDM2 de-ubiquitination and subsequent stabilization, which resulted in the upregulation of the Bad phosphorylation. Additionally, we also found that USP7 might induce cell epithelial-mesenchymal transition to enhance the cell invasive ability. Clinically, USP7 overexpression significantly correlated with malignant phenotype. Furthermore, the 5-year overall survival in patients with USP7(low) was higher than that of USP7(high). Multivariate analysis showed USP7 overexpression was an independent prognostic marker for these cancers. USP7 overexpression may regulate the survival and invasive properties of squamous cell carcinoma and large cell carcinoma cells, and may serve as a molecular target.
Subject(s)
Carcinoma, Large Cell/metabolism , Carcinoma, Squamous Cell/metabolism , Lung Neoplasms/metabolism , Ubiquitin Thiolesterase/biosynthesis , Animals , Carcinoma, Large Cell/genetics , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Squamous Cell/genetics , Cell Line, Tumor , Down-Regulation , Epithelial-Mesenchymal Transition/genetics , Female , Humans , Lung Neoplasms/genetics , Lymphatic Metastasis/diagnosis , Lymphatic Metastasis/genetics , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Prognosis , Proto-Oncogene Proteins c-mdm2/genetics , Tumor Suppressor Protein p53/genetics , Ubiquitin Thiolesterase/genetics , Ubiquitin-Specific Peptidase 7 , Up-RegulationABSTRACT
Tumor recurrence and metastasis after surgery are the leading causes of death in patients with esophageal squamous cell carcinoma (ESCC). Next-generation sequencing techniques have improved our understanding of the genetic alterations underlying tumor initiation and progression. To explore recurrence-specific transcriptional profiles, functional properties, and gene co-expression networks in ESCC, samples from recurrence (n = 4) and nonrecurrence (n = 4) groups were analyzed by RNA sequencing. Patients included in the nonrecurrence group had five or more years of survival without any evidence of recurrence or metastasis, while those included in the recurrence group exhibited early recurrence and metastasis and died within 2 years. We identified 533 significantly differentially expressed protein-coding and noncoding genes. Functional enrichment analysis indicated that ESCC recurrence was related to dysregulated cell-cell adherence, microenvironment homeostasis, information processing, and the immune response. Co-expression networks demonstrated differences in the patterns of gene expression and co-expression between the recurrence and nonrecurrence groups. This study provided important insights into ESCC progression and the differentially expressed genes that may represent potential targets for ESCC diagnosis and therapy.