Identification and characterization of karyopherin a-2, a nuclear export protein in lung adenocarcinoma.

person Seoree Kim Division of Medical HematoOncology, Department of Internal Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, Bucheon-Si, South Korea info_outline Seoree Kim, Heejin Lee, Jung-Sook Yoon, Joon Won Jeong, Ji Hyun Lee, Sang Hoon Chun, Hye Sung Won, Soon Auck Hong, Keunsoo Kang, Young-Ho Ahn, Yoon Ho Ko, Hojung An

Authors person Seoree Kim Division of Medical HematoOncology, Department of Internal Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, Bucheon-Si, South Korea info_outline Seoree Kim, Heejin Lee, Jung-Sook Yoon, Joon Won Jeong, Ji Hyun Lee, Sang Hoon Chun, Hye Sung Won, Soon Auck Hong, Keunsoo Kang, Young-Ho Ahn, Yoon Ho Ko, Hojung An Organizations Division of Medical HematoOncology, Department of Internal Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, Bucheon-Si, South Korea, Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea, Uijeongbu St. Mary’s Hospital Clinical Research Laboratory, The Catholic University of Korea, Seoul, South Korea, Division of Oncology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea, Bucheon St. Mary's Hospital, Gyeonggi-Do, South Korea, Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Uijeongbu-Si, Gyeonggi-Do, South Korea, Department of Pathology, College of Medicine, Chung-Ang University, Seoul, South Korea, Department of Microbiology, College of Science & Technology, Dankook University, Seoul, South Korea, Department of Molecular Medicine and Inflammation-Cancer Microenvironment Research Center, College of Medicine, Ewha Womans University, Seoul, South Korea, Division of Oncology, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, Catholic University, Seoul, South Korea, Stanford University Medical Center, Suwon-Si, CA, South Korea Abstract Disclosures Research Funding No funding received None. Background: It is emerging that the Karyopherin a-2 (KPNA2), a nucleocytoplasmic transport protein, regulates the nuclear import of macromolecules and contributes to carcinogenesis and changes in cellular phenotype. In particular, it can be a poor prognostic marker by causing aberrant subcellular localization of DNA damage response proteins or OCT4-c MYC pathway molecules depending on the type of carcinoma and inducing anticancer resistance. In some carcinomas, an association with the p53 oncogenic pathway has been reported, showing good prognostic values. We aimed to investigate the clinical significance and metabolic pathway of stable cancer associated fibroblast (CAF) and cancer cells for KPNA2. Methods: We retrospectively analyzed the data extracted from EMR for NSCLC patients receiving curative surgical resection in Uijeongbu and Bucheon St. Mary’s Hospitals (n = 165). Immunohistochemistry staining was performed on the tumor microarray samples using antibodies against KPNA2. The functional assay and gene silencing was conducted. Results: Based on the TMA staining, mean KPNA2 score was 36.5 [0-240] and median value was 10. The clinical and pathological information of the experimental group is as follows. Table 1. Scatter plots and correlation between KPNA2 expression levels and tumor invasiveness markers reveals that high KPNA2 expressor was related to lymphatic invasion (p = 0.00782), advanced stage (p = 0.0202) and current smoker (p = 0.0074). KPNA2 expression was higher in squamous cell carcinoma(SqCC) histotype than in adenocarcinoma (SqCC ratio (%), 13.5 vs 43.4 in Low exp vs High exp; p = 0.007). Patients with high expression of KPNA2 showed shorter survival than other patients (median OS (months), 72.8 vs 42.2, P < 0.0001; median RFS (months), 72.8 vs 32.1, P < 0.0011) and relevant to high recurrence (recurrence rate (%), 24.7 vs 44.7, p = 0.007). Further, high KPNA2 expression was associated with poor survival outcomes. To test the effect of KPNA2 on cancer cell invasion, we knocked down Kpna2 via shRNA. Spheroids composed of H1299, Calu-6, A549, HCC827 lung cancer cells with either Kpna2-overexpression or Kpna2-knockdown, and spheroid invasion was then monitored for two days. Eminently, the 3-D invasion of spheroids was suppressed via Kpna2 knockdown. In addition, Kpna2-overexpressing cells promoted cancer invasion to a greater extent than control. Conclusions: In conclusion, our results suggest that KPNA2 protein expression has a poor prognostic association, revealed by its association with survival outcome or invasiveness markers. Its clinical significance as an oncogenic target molecule is emerging, and further evaluation using an organoid model is in progress.