Regulation of Anti-Apoptotic Protein Flip by Heterogeneous Nuclear Ribonucleoprotein K in Nasopharyngeal Carcinoma

  • Chen, Lih-Chyang (PI)

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Our previous work indicated that overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K) can prevent hypoxia-induced apoptosis through the induction of thymidine phosphorylase and plays an independent poor prognostic factor in the patients with nasopharyngeal carcinoma (NPC). However, a genome wide study for hnRNP K targets is still limited. Using Affymetrix approach, our unpublished data showed that 363 genes elevated in NPC tissues compared with adjacent normal tissues in vivo and downregulated after hnRNP K knockdown in NPC-TW02 cells in vitro were potential targets for hnRNP K-mediated positive regulation. Since the function of hnRNP K was involved in anti-apoptosis and metastasis, two category genes involved in cell survival including FLIP, DcR3, Rad9B, and IL7R; and cell migration including RANTES, MMP13, ITGB6, and Rap2A were further validated using quantitative RT-PCR. Compare with NPC-TW02 cells transfected with control siRNA, the mRNA levels of FLIP, MMP13, ITGB6, Rad9B, and Rap2A were significantly inhibited to 0.2, 0.4, 0.4, 0.3, and 0.8 fold by hnRNP K knockdown respectively. Consistently, FLIP protein was obviously reduced after hnRNP K knockdown. Since FLIP, an important inhibiter for TRAIL-induced apoptosis, is significantly controlled by hnRNP K, but is less studied in NPC; we have further analyzed the expression of FLIP and hnRNP K immunohistochemically in 67 clinically proven NPC cases. FLIP was highly expressed in tumor cells, but weakly expressed in normal nasopharyngeal epithelium. High level of FLIP expression (60%) was significantly correlated with nuclear hnRNP K (P = 0.002) and associated with poor overall survival (OS; P = 0.015). A multivariate analysis confirmed that high FLIP was independent prognostic predictor for OS (P = 0.005). Taken together, the expression of FLIP is regulated by hnRNP K in vitro and in vivo, and affects OS of NPC patients. Identifying the mechanisms for hnRNP K-mediated FLIP regulation not only elucidates the molecular pathogenesis of NPC, but also allows us to develop hnRNP K- and FLIP-targeted therapies. Therefore, the aims of this proposal are (1) to study the molecular mechanisms involved in hnRNP K-mediated FLIP expression; (2) to identify the role of hnRNP K protein complex-associated proteins in FLIP regulation; and (3) to examine the biological function of hnRNP K-mediated FLIP expression to TRAIL-induced apoptosis in NPC cells.

Project IDs

Project ID:PC10001-0024
External Project ID:NSC99-2321-B182-005-MY2
StatusFinished
Effective start/end date01/01/1131/12/11

Keywords

  • FLIP
  • hnRNP K
  • nucleolin
  • prognosis
  • nasopharyngeal carcinoma

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