Prognostic and therapeutic impact of RPN2-mediated tumor malignancy in non-small-cell lung cancer.

Abstract

RNA interference (RNAi) is a powerful gene-silencing platform for cancer treatment. Previously, we demonstrated that ribophorin II (RPN2), which is part of the N-oligosaccharyl transferase complex, regulates docetaxel sensitivity and tumor lethal phenotypes in breast cancer. However, the molecular functions and clinical relevance of RPN2 in non-small-cell lung cancer (NSCLC) remain unknown. Here, we examined RPN2 expression in tumor specimens from recurrent NSCLC patients after resection (n = 32 and = 177) and assessed the correlation between RPN2 expression and various clinical features. We also investigated whether RPN2 affects cancer malignancy in vitro and tumor growth and drug resistance in vivo. Our data show that RPN2 expression confers early and distant recurrence as well as poor survival in NSCLC patients. Furthermore, RPN2 silencing suppressed cell proliferation and invasiveness, and increased the sensitivity to chemotherapeutic drugs in vitro. Remarkably, we found that intrinsic apoptosis signaling is the mechanism of cell death involved with RPN2 knockdown. Strikingly, RPN2 silencing repressed tumorigenicity and sensitized the tumors to cisplatin treatment, which led to the longer survival of NSCLC-bearing mice. In conclusion, these data suggest that RPN2 is involved in the regulation of lethal cancer phenotypes and represents a promising new target for RNAi-based medicine against NSCLC.

• Authors: Yu Fujita, Shigehiro Yagishita, Fumitaka Takeshita, Yusuke Yamamoto, Kazuyoshi Kuwano, Takahiro Ochiya
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 5 Pg. 3335-45 (Feb 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25595901 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Hexosyltransferases
• RPN2 protein, human
• Proteasome Endopeptidase Complex
• Cisplatin

Topics

• Adult
• Aged
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Carcinoma, Non-Small-Cell Lung (enzymology, genetics, mortality, pathology, therapy)
• Cell Line, Tumor
• Cell Proliferation
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm
• Female
• Gene Expression Regulation, Neoplastic
• Hexosyltransferases (genetics, metabolism)
• Humans
• Lung Neoplasms (enzymology, genetics, mortality, pathology, therapy)
• Male
• Mice, SCID
• Middle Aged
• Neoplasm Invasiveness
• Neoplasm Recurrence, Local
• Phenotype
• Pneumonectomy
• Proteasome Endopeptidase Complex (genetics, metabolism)
• RNA Interference
• RNAi Therapeutics
• Time Factors
• Transfection
• Treatment Outcome
• Xenograft Model Antitumor Assays