Study the Molecular Mechanisms Responsible for Overexpression and Nuclear Accumulation of Oncogenic Kpna2 in Lung Cancer Cells

Shuttling of specific proteins into (import) and out (export) of the nucleus, termed nucleocytoplasmic transport is essential for the precise regulation of cellular processes in normal and also malignant cells. Karyopherin alpha 2 (KPNA2, importin α1) delivers classical nuclear localization sequence (cNLS)-containing cargo proteins to the nucleus, followed by translocation back into cytoplasmic compartments. Aberrant KPNA2 expression has been observed in numerous types of human cancer tissues and is associated with poor prognosis in patients. Previously, we identified KPNA2 as a potential biomarker for non-small cell lung cancer (NSCLC) [1]. We also identified E2F1 as a novel cargo of KPNA2 [2] and we have demonstrated that the high level of KPNA2-vimentin-pErk complex was associated with lung cancer invasiveness [3]. Nevertheless, the upstream signal responsible for KPNA2 overexpression and its nuclear accumulation in cancer cells remain unclear. Whether KPNA2 can serve the novel roles which are different from its well-known nuclear transport is also need to be clarified. In this proposal, we aim to study the upstream signaling, the transcriptional regulation and the molecular mechanisms responsible for the dysregulated KPNA2 in cancer cells. Our preliminary data show that 1) mTOR signaling modulated KPNA2 expression in lung and breast cancer cells; 2) E2F1/Dp1 and IRF1 were potential transcription factors (TFs) responsible for KPNA2 gene expression; 3) EGF and oxidative stress induced the nuclear accumulation and complex formation of KPNA2 in cancer cells; 4) KPNA2 was identified as a multiple phosphorylated protein and the phosphorylation would regulate its subcellular localization. Our hypothesis is that the post-translational modifications (PTMs) as well as KPNA2-interacting proteins, both cNLS-containing and cNLS-free proteins contribute to KPNA2-mediated tumorigenesis. The objective of this proposal is to understand the fundamental basis of the spatiotemporal regulation of KPNA2 functional complexes formation and to develop the potential therapeutic target to suppress KPNA2-mediated tumorigenesis. Our specific aims include: 1. Investigate the upstream signaling and TFs responsible for KPNA2 overexpression in NSCLC. 2. Investigate the molecular mechanisms including PTMs and protein-protein interactions responsible for nuclear accumulation of KPNA2 complexes in cancer cells. 3. Study the cargo-dependent and cargo-independent mechanisms of KPNA2-mediated tumorigenesis. 4. Search the potential therapeutic targets to specifically suppress overexpression or attenuate nuclear import through KPNA2 in cancer cells. The expected impact on social and academic development after the implementation of this project include: (1) it will help our understanding of the underling mechanisms of KPNA2 overexpression in human cancers; (2) it provides the knowledge and methods applied to study the spatiotemporal regulation of KPNA2 complex formation and its role in tumorigenesis; (3) it provides the basis to develop a novel therapeutic target of cancer by modulating the nucleocytoplasmic transport.

Project ID:PC10601-1055
External Project ID:MOST105-2320-B182-035-MY3