ABSTRACT
SNRPB is a core component of spliceosome and plays a major role in regulating alternative splicing of the pre-mRNA. However, little is known about its role in cancer to date. In this study, we observe that SNRPB is overexpressed in NSCLC and correlated with poor prognosis in patients with NSCLC. We demonstrate that SNRPB promotes NSCLC tumorigenesis both in vitro and in vivo. Mechanistically, we reveal that RAB26 is a critical target of SNRPB. Suppression of SNRPB leads to retention of intron seven in the RAB26 mRNA and reduced RAB26 mRNA through activation of nonsense-mediated RNA decay (NMD). Moreover, forced expression of RAB26 partially restores the decreased tumorigenicity in NSCLC cells with SNRPB depletion. Our study unveils a novel role of SNRPB in facilitating NSCLC tumorigenesis via regulation of RAB26 expression and proposes that the SNRPB/RAB26 pathway may offer a therapeutic vulnerability in NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/metabolism , rab GTP-Binding Proteins/metabolism , snRNP Core Proteins/metabolism , Alternative Splicing/genetics , Animals , Carcinogenesis/genetics , Carcinogenesis/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/secondary , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Humans , Introns , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Nonsense Mediated mRNA Decay/genetics , Transplantation, Heterologous , rab GTP-Binding Proteins/genetics , snRNP Core Proteins/geneticsABSTRACT
The small-interfering RNAs (siRNAs) have been employed to knockdown the expression of cancer-associated genes and shown some promise in cancer therapy. However, synthetic siRNA duplexes or plasmid mediated delivery of siRNAs have several problems, such as short half-life, low transfection efficiency and cytotoxicity associated with transfection. Conditionally replicating adenovirus (CRAds) as the delivery vector for short hairpin RNAs (shRNAs) could overcome these limitations and have shown augmented anti-tumor effects in experimental studies and preclinical trials. In this review, we summarize recent progress in the development of CRAds-shRNA for cancer treatment. Combination of CRAds-shRNA with chemotherapeutics, radiation, dendritic cells, monoclonal antibodies and small-molecule inhibitors will be necessary to eradicate cancer cells and cancer stem cells and achieve superior outcomes. The use of CRAd platform for efficient delivery of shRNAs and foreign genes will open a new avenue for cancer therapy.
