Overexpression of CRM1: A Characteristic Feature in a Transformed Phenotype of Lung Carcinogenesis and a Molecular Target for Lung Cancer Adjuvant Therapy

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Overexpression of CRM1: A Characteristic Feature in a Transformed Phenotype of Lung Carcinogenesis and a Molecular Target for Lung Cancer Adjuvant Therapy

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Overexpression of CRM1: A Characteristic Feature in a Transformed Phenotype of Lung Carcinogenesis and a Molecular Target for Lung Cancer Adjuvant Therapy Weimin Gao, MD, PhD, Chuanwen Lu, PhD, Lixia Chen, MD, PhD, Phouthone Keohavong, PhD Journal of Thoracic Oncology Volume 10, Issue 5, Pages 815-825 (May 2015) DOI: 10.1097/JTO.0000000000000485 Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 CRM1 expression in lung tumors from human lung cancer patients and NNK-induced lung adenocarcinoma in mice. A, IHC staining of CRM1 in lung adenocarcinoma and matched adjacent histologically normal lung tissues from a lung cancer patient (40×). B, Quantitive H score of CRM1 expression in lung tumors and matched adjacent normal lung tissues (n = 10). *p < 0.01 compared with adjacent normal. C, Quantitative measurement of CRM1 expression in lung tumors and matched adjacent normal lung tissues from tissue microarray (n = 59). *p < 0.01 compared with adjacent normal. D, Hematoxylin and eosin staining (40×) of a case of lung adenocarcinoma from NNK-treated mice. E, CRM1 protein expression of four representative cases of lung adenocarcinoma from NNK-treated mice (n = 8) and four representative normal lung tissues from vehicle-treated controls (n = 8) from the same Western blot. The blot was probed for α-tubulin to confirm equal protein loading. *p < 0.01 compared with the control. CRM1, chromosome region maintenance 1; IHC, immunohistochemistry. Journal of Thoracic Oncology 2015 10, 815-825DOI: (10.1097/JTO.0000000000000485) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Soft agar colony assay and CRM1 and phospho-p53 expressions in BEAS-2B cells after NNK exposure. A, Soft agar colony assay of BEAS-2B cells and NNK-transformed BEAS-2B cells (BEAS-2BNNK; 40×). B, CRM1 and phospho-p53 (Thr55) protein expression in BEAS-2B cells and BEAS-2BNNK cells. *p < 0.05 compared with BEAS-2B. C, Phospho-p53 (Thr55) protein expression of four representative cases of lung adenocarcinoma from NNK-treated mice (n = 8) and four representative normal lung tissues from vehicle-treated controls (n = 8) from the same Western blot. The blot was probed for α-tubulin to confirm equal protein loading. *p < 0.01 compared with the control. D, Phospho-p53 (Thr55) expression in BEAS-2B cells exposed to NNK or vehicle control for 24 and 72 h. Data were obtained from representative samples loaded on the same Western blot for each of 24 and 72 h. Blots were probed for α-tubulin to confirm equal protein loading. *p < 0.05 compared with the control. CRM1, chromosome region maintenance 1. Journal of Thoracic Oncology 2015 10, 815-825DOI: (10.1097/JTO.0000000000000485) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 CRM1 protein expression and soft agar colony assay in BEAS-2B, BEAS-2BCRM1+, A549, and A549CRM1- cells, and tumor growths in xenograft nude mice implanted with A549 or A549CRM1- cells. A–C, CRM1 protein expression (A), cell morphology (B, 100×), and soft agar colony assay (C, 40×) in BEAS-2B and BEAS-2BCRM1+ cells. The blot was probed for α-tubulin to confirm equal protein loading. *p < 0.01 compared with BEAS-2B. D–F, CRM1 protein expression after CRM1-siRNA (D) and CRM1-shRNA (E) transfection and soft agar colony assay (F, 40×) in A549 and A549CRM1- cells. Blots were probed for α-tubulin to confirm equal protein loading. *p < 0.05 compared with A549. G, Tumor growths in xenograft nude mice (strain code 088) implanted with A549 or A549CRM1- cells. CRM1, chromosome region maintenance 1; shRNA, short hairpin siRNA. Journal of Thoracic Oncology 2015 10, 815-825DOI: (10.1097/JTO.0000000000000485) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 The effects of Cis and/or LMB on cytotoxicity and cell cycle distribution. A, Cytotoxic effects of Cis on A549 or A549CRM1- cells at 24–72 h. Data are expressed as the percentage by comparing to vehicle control. Values are represented as mean ± SD, n = 6. Experiments performed in triplicate yielded similar results. B, Cytotoxic effects of Cis and/or LMB on A549 cells at 24–72 h. Data are expressed as the percentage by comparing with vehicle control for Cis and LMB for Cis + LMB. Values are represented as mean ± SD, n = 6. Experiments performed in triplicate yielded similar results. C, Distribution of cell population in different cell cycle phases in A549 after Cis and/or LMB treatment. Experiments were performed in triplicate and yielded similar results. Cis25: 25 μM cisplatin, LMB0.5: 0.5 nM LMB, and Cis25 + LMB0.5: 25 μM cisplatin + 0.5 nM LMB. LMB, leptomycin B; CRM1, chromosome region maintenance 1. Journal of Thoracic Oncology 2015 10, 815-825DOI: (10.1097/JTO.0000000000000485) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 The effects of Cis and/or LMB on gene/protein expression. A, A representative PCR array gene table and RT-PCR gene arrays in A549 cells treated with Cis or Cis + LMB. The heat map demonstrating fold regulation expression data. Gray Genes were not measurable. Cis25: 25 μM cisplatin, and Cis25 + LMB0.5: 25 μM cisplatin + 0.5 nM LMB. B, Western blot analyses of PARP1, p21, and survivin protein expression in A549 cells after Cis and/or LMB treatment. Blots were probed for α-tubulin to confirm equal protein loading. RT-PCR, reverse transcription-polymerase chain reaction. LMB, leptomycin B. Journal of Thoracic Oncology 2015 10, 815-825DOI: (10.1097/JTO.0000000000000485) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 6 The effects of Cis and/or LMB on tumor growth (A) and body weight (B) in xenografted nude mice (strain code 088). The Cis-treated group showed a significant decrease in tumor growth compared with the vehicle treated group. The Cis + LMB group demonstrated a significant decrease in tumor growth compared with the Cis-treated group. Vehicle control: 0.9% saline (n = 8), LMB: 2 μg/kg (n = 8), Cis: 2.5 mg/kg (n = 8), and Cis + LMB: Cis (2.5 mg/kg) + LMB (2 μg/kg; n = 8). LMB, leptomycin B. Journal of Thoracic Oncology 2015 10, 815-825DOI: (10.1097/JTO.0000000000000485) Copyright © 2015 International Association for the Study of Lung Cancer Terms and Conditions