Faculty Profiles - SHIEN Kazuhiko

Papers - SHIEN Kazuhiko

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Silenced expression of NFKBIA in lung adenocarcinoma patients with a never-smoking history. Reviewed

Furukawa M, Soh J, Yamamoto H, Ichimura K, Shien K, Maki Y, Muraoka T, Tanaka N, Ueno T, Asano H, Tsukuda K, Toyooka S, Miyoshi S

Acta medica Okayama 67 ( 1 ) 19 - 24 2013.1

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Nuclear factor of κ-light polypeptide gene enhancer in B cells inhibitor α (NFKBIA), which is a tumor suppressor gene, was found to be silenced in lung adenocarcinomas. We examined NFKBIA expression, mutations in the EGFR and K-ras genes, and EML4-ALK fusion in 101 resected lung adenocarcinoma samples from never-smokers. NFKBIA expression was evaluated using immunohistochemistry. NFKBIA expression was negative in 16 of the 101 samples (15.8%). EGFR and K-ras mutations and EML4-ALK fusion were detected in 61 (60.5%), 1 (1.0%), and 2 (2.0%) of the 101 samples, respectively, in a completely mutually exclusive manner. Negative NFKBIA expression was observed significantly more frequently among the tumors with none of the three genetic alterations compared to those with such alterations (p = 0.009). In addition, negative NFKBIA expression was significantly more frequent among the EGFR-wild type samples compared to the EGFR-mutant samples (p = 0.013). In conclusion, NFKBIA expression was silenced in adenocarcinomas without EGFR/K-ras mutations or EML4-ALK fusion, suggesting that the silencing of NFKBIA may play an important role in the carcinogenesis of adenocarcinomas independent of EGFR/K-ras mutations or EML4-ALK fusion.

DOI： 10.18926/amo/49253

Use of a vessel sealing system versus conventional electrocautery for lung parenchymal resection: a comparison of the clinicopathological outcomes in porcine lungs Reviewed

Sugimoto, S., Toyooka, S., Iga, N., Furukawa, M., Sugimoto, R., Shien, K., Nishikawa, H., Soh, J., Yamane, M., Oto, T., Miyoshi, S.

Surg Today 44 ( 3 ) 540 - 5 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

PURPOSE: LigaSure, a vessel sealing system, has been shown to have excellent hemostatic properties; however, its use for lung parenchymal resection has been limited. We herein examined the hemostatic properties and potential for inducing histological lung injury of the LigaSure system in non-anatomic pulmonary resection to estimate the feasibility of its clinical application. METHODS: Non-anatomic pulmonary wedge resections of the right cranial, middle, and caudal lobes were performed in four pigs using the LigaSure system (Group A) or electrocautery (Group B). In each resection, the resection time, blood loss, and weight of the resected lung were measured. The thermal effect on the lung tissue was examined by means of intraoperative thermography and histology. RESULTS: A total of 12 lung wedge resections were performed in each group. For an equivalent length of operation and weight of the resected lung parenchyma, Group A showed significantly lower blood loss and lower maximum and minimum temperatures of the lung tissue, as assessed by thermography, than Group B. The degree of thermal injury as estimated by a histological examination was lower in Group A than in Group B. CONCLUSION: Our study suggests that the LigaSure system may be superior to conventional electrocautery, indicating its clinical usefulness for non-anatomic pulmonary resection.

DOI： 10.1007/s00595-013-0545-1

The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma Reviewed International journal

Muraoka, T., Soh, J., Toyooka, S., Aoe, K., Fujimoto, N., Hashida, S., Maki, Y., Tanaka, N., Shien, K., Furukawa, M., Yamamoto, H., Asano, H., Tsukuda, K., Kishimoto, T., Otsuki, T., Miyoshi, S.

Lung Cancer 82 ( 3 ) 485 - 90 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

OBJECTIVES: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. microRNA-34b/c (miR-34b/c), which plays an important role in the pathogenesis of MPM, is frequently downregulated by DNA methylation in approximately 90% of MPM cases. In this study, we estimated the degree of miR-34b/c methylation in serum-circulating DNA using a digital methylation specific PCR assay (MSP). MATERIALS AND METHODS: A real-time MSP assay was performed using the SYBR Green method. The melting temperature (Tm) of each PCR product was examined using a melting curve analysis. For a digital MSP assay, 40 wells were analyzed per sample. A total of 110 serum samples from 48 MPM cases, 21 benign asbestos pleurisy (BAP) cases, and 41 healthy volunteers (HVs) were examined. RESULTS: Positive range of Tm value for miR-34b/c methylation was defined as 77.71-78.79 °C which was the mean ± 3 standard deviations of 40 wells of a positive control. The number of miR-34b/c methylated wells was counted per sample according to this criterion. The number of miR-34b/c methylated wells in MPM cases was significantly higher than that in BAP cases (P=0.03) or HVs (P<0.001). Advanced MPM cases tended to have higher number of miR-34b/c methylated wells than early MPM cases. Receiver-operating characteristic (ROC) curve analysis revealed that three number of miR-34b/c methylated wells per sample was the best cut-off of positivity of MPM with a 67% of sensitivity and a 77% specificity for prediction. The area under the ROC curve was 0.77. CONCLUSIONS: Our digital MSP assay can quantify miR-34b/c methylation in serum-circulating DNA. The degree of miR-34b/c methylation in serum-circulating DNA is associated with MPM, suggesting that this approach might be useful for the establishment of a new detection system for MPM.

DOI： 10.1016/j.lungcan.2013.09.017

Impact of GLUT1 and Ki-67 expression on early‑stage lung adenocarcinoma diagnosed according to a new international multidisciplinary classification Reviewed International journal

Maki, Y., Soh, J., Ichimura, K., Shien, K., Furukawa, M., Muraoka, T., Tanaka, N., Ueno, T., Yamamoto, H., Asano, H., Tsukuda, K., Toyooka, S., Miyoshi, S.

Oncol Rep 29 ( 1 ) 133 - 40 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

High expression levels of glucose transporter isoform 1 (GLUT1) and Ki-67 are reportedly associated with malignancy-related clinicopathological factors in malignant tumors. Recently, a new histological IASLC/ATS/ERS classification for lung adenocarcinoma was proposed. In this study, we investigated the clinicopathological impact of GLUT1 and Ki-67 expression on early-stage lung adenocarcinoma classified according to the IASLC/ATS/ERS classification. One hundred and five patients with completely resected stage IA lung adenocarcinoma were retrospectively classified into two groups, a 'non-invasive type' (n=31) or an 'invasive type' (n=74), based on the IASLC/ATS/ERS classification. GLUT1 and Ki-67 expression status was evaluated using immunohistochemistry. The epidermal growth factor receptor (EGFR) and KRAS mutation status was determined using PCR-based assays. Positive GLUT1 and Ki-67 expression and EGFR and KRAS mutations were detected in 28 (27%), 33 (31%), 51 (49%) and 5 (8%) cases, respectively. Positive GLUT1 expression was significantly associated with a wild-type EGFR and mutant KRAS status. A multivariate analysis revealed that positive GLUT1 expression was independently associated with the 'invasive type'. In multivariate analyses for overall survival (OS) and disease-free survival (DFS), positive Ki-67 and GLUT1 expression was the only independent factor for a poor OS (P=0.012) and DFS (P=0.040), respectively. In addition, when stratified according to the GLUT1 and Ki-67 status, double-positive cases had the poorest DFS and OS times, compared with the other categories. Positive GLUT1 expression is associated with the invasive character of early-stage lung adenocarcinoma and with early disease relapse. Our results strongly suggest that GLUT1 and Ki-67 play important roles in acquiring biological malignant potential in early-stage lung adenocarcinoma.

DOI： 10.3892/or.2012.2087

Sacrificing the pulmonary arterial branch to the spared lobe is a risk factor of bronchopleural fistula in sleeve lobectomy after chemoradiotherapy Reviewed International journal

Toyooka, S., Soh, J., Shien, K., Sugimoto, S., Yamane, M., Oto, T., Date, H., Miyoshi, S.

Eur J Cardiothorac Surg 43 ( 3 ) 568 - 72 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

OBJECTIVES: A sleeve lobectomy is a widely accepted procedure for enabling the pulmonary parenchyma to be spared. Induction chemoradiotherapy (CRT) followed by surgery is one treatment option for locally advanced non-small cell lung cancer (NSCLC), but CRT is considered to have a negative effect on subsequent surgery, especially for anastomotic healing. In this study, we describe our experience performing sleeve lobectomies and the associated anastomotic complications after induction CRT. METHODS: The medical records of NSCLC patients who underwent surgery after receiving CRT were reviewed. The relationships between anastomotic complications and clinicopathological factors were examined. RESULTS: Between December 1998 and October 2011, a total of 104 patients received CRT followed by surgery. Among them, 14 NSCLC patients underwent a bronchial sleeve resection: nine patients underwent a right upper lobe resection, two patients underwent a left lingular division and lower lobe resection and one patient each underwent a right lower lobe, a right upper and middle lobe and a right middle and lower lobe resection. A bronchopleural fistula at the anastomosis occurred in two patients. A pulmonary arterial (PA) branch to the spared lobe had been sacrificed in both of these patients because of tumour involvement. In contrast, the PA branches to the spared lobes were preserved in 11 of the 12 patients who did not exhibit anastomotic complications (P = 0.033). CONCLUSIONS: Our experience strongly suggests that the sacrifice of the PA branch to the spared lobe is a possible risk factor for anastomotic complications for a sleeve lobectomy after induction CRT.

DOI： 10.1093/ejcts/ezs323

Impact of aberrant methylation of microRNA-9 family members on non-small cell lung cancers Reviewed International journal

Muraoka, T., Soh, J., Toyooka, S., Maki, Y., Shien, K., Furukawa, M., Ueno, T., Tanaka, N., Yamamoto, H., Asano, H., Tsukuda, K., Miyoshi, S.

Mol Clin Oncol 1 ( 1 ) 185 - 189 2013

Language：English Publishing type：Research paper (scientific journal)

MicroRNAs (miRs) contribute to cancer development and progression by acting as oncogenes and tumor suppressor genes. miR-9 family members (miR-9s), including miR-9-1, 9-2 and 9-3, have been shown to be oncogenically involved through the downregulation of E-cadherin expression, which promotes the epithelial-mesenchymal transition. Tumor suppressive roles of miR-9s have also been reported to silence miR-9 through methylation, which is associated with an shortened overall survival (OS) period in several types of cancer. In this study, the impact of miR-9s methylation on non-small cell lung cancers (NSCLC) was investigated. In total, 293 resected NSCLC samples were examined and the miR-9s methylation status was determined using a combined bisulfite restriction analysis. miR-9 expression was analyzed by in situ hybridization. Methylation of miR-9-1, 9-2 and 9-3 was present in 20 (7%), 33 (11%) and 34 (12%) of the cases, respectively. Methylation of any miR-9s (miR-9s methylation) was observed in 76 of the cases (26%), and miR-9 expression was silenced in cases with miR-9s methylation. Logistic regression analysis demonstrated that male gender [odds ratio (OR), 2.0; 95% confidence interval (95% CI), 1.1-3.6; P=0.01] and pathologically negative lymph node metastasis (OR, 4.8; 95% CI, 1.4-17.2; P=0.002) were independent relative factors for miR-9s methylation. Additionally, miR-9s methylation [hazard ratio (HR), 4.2; 95% CI, 1.2-27.0; P=0.026] and early pathological stage (HR, 8.3; 95% CI, 2.1-28.6; P=0.004) were found to be independent predictive factors for prolonged OS time by the Cox proportional hazard test. miR-9s methylation which induces expression silencing is common in NSCLC cases without lymph nodal metastasis, suggesting that miR-9s are oncogenically involved in NSCLC carcinogenesis through the promotion of tumor metastasis.

DOI： 10.3892/mco.2012.18

Acquired Resistance to EGFR Inhibitors Is Associated with a Manifestation of Stem Cell-like Properties in Cancer Cells Reviewed International journal

Shien, K., Toyooka, S., Yamamoto, H., Soh, J., Jida, M., Thu, K. L., Hashida, S., Maki, Y., Ichihara, E., Asano, H., Tsukuda, K., Takigawa, N., Kiura, K., Gazdar, A. F., Lam, W. L., Miyoshi, S.

Cancer Res 73 ( 10 ) 3051 - 61 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) is a critical problem in the treatment of lung cancer. Although several mechanisms have been shown to be responsible for acquired resistance, all mechanisms have not been uncovered. In this study, we investigated the molecular and cellular profiles of the acquired resistant cells to EGFR-TKI in EGFR-mutant lung cancers. Four EGFR-mutant cell lines were exposed to gefitinib by stepwise escalation and high-concentration exposure methods, and resistant sublines to gefitinib were established. The molecular profiles and cellular phenotypes of these resistant sublines were characterized. Although previously reported, alterations including secondary EGFR T790M mutation, MET amplification, and appearance of epithelial-to-mesenchymal transition (EMT) features were observed, these 2 drug-exposure methods revealed different resistance mechanisms. The resistant cells with EMT features exhibited downregulation of miRNA-200c by DNA methylation. Furthermore, the HCC827-derived subline characterized by the high-concentration exposure method exhibited not only EMT features but also stem cell-like properties, including aldehyde dehydrogenase isoform 1 (ALDH1A1) overexpression, increase of side-population, and self-renewal capability. Resistant sublines with stem cell-like properties were resistant to conventional chemotherapeutic agents but equally sensitive to histone deacetylase and proteasome inhibitors, compared with their parental cells. ALDH1A1 was upregulated in clinical samples with acquired resistance to gefitinib. In conclusion, our study indicates that the manner of EGFR-TKI exposure influences the mechanism of acquired resistance and the appearance of stem cell-like property with EGFR-TKI treatment.

DOI： 10.1158/0008-5472.CAN-12-4136

Downregulation of microRNA-34 induces cell proliferation and invasion of human mesothelial cells Reviewed International journal

Tanaka, N., Toyooka, S., Soh, J., Tsukuda, K., Shien, K., Furukawa, M., Muraoka, T., Maki, Y., Ueno, T., Yamamoto, H., Asano, H., Otsuki, T., Miyoshi, S.

Oncol Rep 29 ( 6 ) 2169 - 74 2013

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Malignant mesothelioma (MM) is an aggressive tumor with a dismal prognosis, and the molecular alterations involved in this disease remain unknown. We previously reported that microRNA-34s (miR-34s) are methylated and downregulated in MM and may play an important role in the carcinogenesis of MM. In this study, we downregulated miR-34s in human mesothelial cells to investigate the cellular effect of miR-34 knockdown. For the cell study, we used LP-9, a human mesothelial cell line, and three human primary-cultured mesothelial cell lines. RNA-based miR-34a, -34b and -34c inhibitors were transfected into these cells, and their effects on proliferation and invasion were evaluated. A scramble RNA oligonucleotide was used as a control. The protein expression status was estimated using western blotting. After miR-34 inhibitor transfection, miR-34a, -34b and -34c were downregulated in all the examined mesothelial cell lines. miR-34 inhibitor transfection significantly increased cell proliferation in all of the mesothelial cell lines, compared with the scramble control. The invasive ability also increased in the miR-34 inhibitor transfectants, compared with the scramble control, in the LP-9 cell line. Western blotting confirmed the upregulation of c-MET, phospho-c-MET, and bcl-2 proteins in LP-9 cells after miR-34 inhibitor transfection. In conclusion, our study showed that the downregulation of miR-34s induced an oncogenic phenotype in non-malignant mesothelial cells. The present study, together with the results of our previous report, strongly suggest that miR-34s play an important role in the early carcinogenic process involved in the transformation of human mesothelial cells to MM.

DOI： 10.3892/or.2013.2351

Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer Reviewed International journal

Norimitsu Tanaka, Shinichi Toyooka, Junichi Soh, Takafumi Kubo, Hiromasa Yamamoto, Yuho Maki, Takayuki Muraoka, Kazuhiko Shien, Masashi Furukawa, Tsuyoshi Ueno, Hiroaki Asano, Kazunori Tsukuda, Keisuke Aoe, Shinichiro Miyoshi

Lung Cancer 108 254 - 255 2012.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier Ireland Ltd

The publisher regrets errors were introduced in Fig. 3 A of the article described above. The images for both p-Scramble and p-miR-34b/c in SBC5 were incorrect. An amended version of Fig. 3 is shown below. Note that the analyses for both migration and invasion assays were appropriate and thus it is not necessary to correct the bar graphs in Fig. 3 as well as the legends for Fig. 3. The authors also consider that there is no need to correct any other parts of this article. The publisher would like to apologise for any inconvenience caused.

DOI： 10.1016/j.lungcan.2016.04.016

Ectopic cervical thymoma: a case report with 18F-fluorodeoxyglucose positron emission tomography findings. Reviewed

Shien K, Shien T, Soh J, Ikeda H, Nogami T, Taira N, Doihara H, Miyoshi S

Acta medica Okayama 66 ( 4 ) 357 - 61 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Ectopic thymoma is considered to arise from ectopic thymus tissue deposited as a result of the abnormal mislocalization of thymus tissue during the embryonic stage. An 86-year-old man visited our hospital with chief complaints of hoarseness and a mass in his anterior neck. A preoperative needle biopsy of the mass did not yield a definitive diagnosis. A positron emission tomography (PET) study revealed heterogeneous accumulation of (18)F-fluorodeoxyglucose (FDG) in the tumor. The tumor, affecting the left sternocleidomastoid muscle, the recurrent laryngeal nerve, the internal carotid vein, and the brachiocephalic vein, was resected using a combination of a collar incision in the neck and a median incision in the sternum. Immunohistochemically, the tumor was diagnosed as an ectopic thymoma of the neck. To date, only a few cases of ectopic thymoma presenting with FDG accumulation have been reported. Our experience indicates that ectopic thymoma should be kept in mind during the differential diagnosis of neck tumors with FDG accumulation appearing on PET images.

DOI： 10.18926/amo/48691

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1 Reviewed International journal

Ohashi, K., Sequist, L. V., Arcila, M. E., Moran, T., Chmielecki, J., Lin, Y. L., Pan, Y., Wang, L., de Stanchina, E., Shien, K., Aoe, K., Toyooka, S., Kiura, K., Fernandez-Cuesta, L., Fidias, P., Yang, J. C., Miller, V. A., Riely, G. J., Kris, M. G., Engelman, J. A., Vnencak-Jones, C. L., Dias-Santagata, D., Ladanyi, M., Pao, W.

Proc Natl Acad Sci U S A 109 ( 31 ) E2127-33 - E2133 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

Acquired resistance to EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) is inevitable in metastatic EGFR-mutant lung cancers. Here, we modeled disease progression using EGFR-mutant human tumor cell lines. Although five of six models displayed alterations already found in humans, one harbored an unexpected secondary NRAS Q61K mutation; resistant cells were sensitive to concurrent EGFR and MEK inhibition but to neither alone. Prompted by this finding and because RAS/RAF/MEK mutations are known mediators of acquired resistance in other solid tumors (colon cancers, gastrointestinal stromal tumors, and melanomas) responsive to targeted therapies, we analyzed the frequency of secondary KRAS/NRAS/BRAF/MEK1 gene mutations in the largest collection to date of lung cancers with acquired resistance to EGFR TKIs. No recurrent NRAS, KRAS, or MEK1 mutations were found in 212, 195, or 146 patient samples, respectively, but 2 of 195 (1%) were found to have mutations in BRAF (G469A and V600E). Ectopic expression of mutant NRAS or BRAF in drug-sensitive EGFR-mutant cells conferred resistance to EGFR TKIs that was overcome by addition of a MEK inhibitor. Collectively, these positive and negative results provide deeper insight into mechanisms of acquired resistance to EGFR TKIs in lung cancer and inform ongoing clinical trials designed to overcome resistance. In the context of emerging knowledge about mechanisms of acquired resistance to targeted therapies in various cancers, our data highlight the notion that, even though solid tumors share common signaling cascades, mediators of acquired resistance must be elucidated for each disease separately in the context of treatment.

DOI： 10.1073/pnas.1203530109

Frequent methylation and oncogenic role of microRNA-34b/c in small-cell lung cancer Reviewed International journal

Tanaka, N., Toyooka, S., Soh, J., Kubo, T., Yamamoto, H., Maki, Y., Muraoka, T., Shien, K., Furukawa, M., Ueno, T., Asano, H., Tsukuda, K., Aoe, K., Miyoshi, S.

Lung Cancer 76 ( 1 ) 32 - 8 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Small-cell lung cancer (SCLC) is an aggressive tumor with a dismal prognosis among primary lung cancers. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family is comprised of tumor-suppressive miRNAs, and its reduced expression by methylation has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the alteration and tumor-suppressive impact of miR-34s in SCLC. The methylation of miR-34a and miR-34b/c was observed in 4 (36%) and 7 (64%) of 11 SCLC cell lines, respectively. Among the 27 SCLC clinical specimens, miR-34a and miR-34b/c were methylated in 4 (15%) and 18 (67%), respectively. In contrast, 13 (28%) miR-34a methylated cases and 12 (26%) miR-34b/c methylated cases were found in 47 NSCLC primary tumors. The frequency of miR-34b/c methylation was significantly higher in SCLC than in NSCLC (p<0.001). The expressions of miR-34s were reduced in methylated cell lines and tumors and restored after 5-aza-2'-deoxycytidine treatment, indicating that methylation was responsible for the reduced expression of miR-34s. Because the frequency of methylation was higher in miR-34b/c, we focused on miR-34b/c for a functional analysis. We examined the effect of miR-34b/c introduction on cell proliferation, migration and invasion. The transfection of miR-34b/c to two SCLC cell lines (H1048 and SBC5) resulted in the significant inhibition of cell growth, migration, and invasion, compared with control transfectants. Our results indicate that the aberrant methylation of miR-34b/c plays an important role in the pathogenesis of SCLC, implying that miR-34b/c may be a useful therapeutic target for SCLC.

DOI： 10.1016/j.lungcan.2011.10.002

Strong anti-tumor effect of NVP-AUY922, a novel Hsp90 inhibitor, on non-small cell lung cancer Reviewed International journal

Ueno, T., Tsukuda, K., Toyooka, S., Ando, M., Takaoka, M., Soh, J., Asano, H., Maki, Y., Muraoka, T., Tanaka, N., Shien, K., Furukawa, M., Yamatsuji, T., Kiura, K., Naomoto, Y., Miyoshi, S.

Lung Cancer 76 ( 1 ) 26 - 31 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

The anti-tumor activity of a newly developed Hsp90 inhibitor, NVP-AUY922 (AUY922), against non-small cell lung cancer (NSCLC) was examined. Twenty-one NSCLC cell lines were used, the somatic alterations of which were characterized. Cell proliferation was analyzed using a modified MTS assay. Expression of the client proteins was assessed using Western blotting. The cell cycle was analyzed using flow cytometry. The IC50 value of AUY922 for the NSCLC cell lines ranged from 5.2 to 860 nM (median, 20.4 nM). Based on previous data, cells with an IC50 of less than 50 nM were classified as sensitive cells and 19 of the 21 NSCLC cell lines were judged to be sensitive. The IC50 of five malignant pleural mesothelioma (MPM) cell lines revealed that the MPM cells had a significantly higher IC50 value (median, 89.2 nM; range, 22.2-24,100 nM) than the NSCLC cells (p=0.015). There was significant depletion of both the total and phosphorylated client proteins--EGFR, MET, HER2 and AKT--at low drug concentrations (50-100 nM) in drug-sensitive cell lines. Cell-cycle analysis was performed for two sensitive cell lines, H1975 and H838. Following AUY922 treatment, an increase in the sub-G0-G1 cell population, as well as appearance of cleaved PARP expression, indicated the induction of apoptosis. In conclusion, AUY922 was effective against most NSCLC cell lines, independent of the type of known molecular alteration, and appears to be a promising new drug for the treatment of NSCLC.

DOI： 10.1016/j.lungcan.2011.09.011

Knockdown of the epidermal growth factor receptor gene to investigate its therapeutic potential for the treatment of non-small-cell lung cancers Reviewed International journal

Shien, K., Ueno, T., Tsukuda, K., Soh, J., Suda, K., Kubo, T., Furukawa, M., Muraoka, T., Maki, Y., Tanaka, N., Yamamoto, H., Kiura, K., Mitsudomi, T., Toyooka, S., Miyoshi, S.

Clin Lung Cancer 13 ( 6 ) 488 - 93 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：CIG MEDIA GROUP, LP

BACKGROUND: Epidermal growth factor receptor (EGFR) is often overexpressed in non-small-cell lung cancer (NSCLC). Anti-EGFR agents, including EGFR-tyrosine kinase inhibitors are considered to be effective when a drug-sensitive EGFR mutation is present. However, inherent and acquired resistances are major problems of EGFR-targeting therapies. In this study, we performed EGFR knockdown by using small interfering RNAs in NSCLC cell lines to examine the significance of targeting EGFR for NSCLC therapy. METHODS: We treated 13 NSCLC cell lines, including 8 EGFR mutant and 5 EGFR wild type by using gefitinib or small interfering RNAs against EGFR (siEGFR). Three cell lines (PC-9-GR1, RPC-9, and HCC827-ER) were experimentally established with acquired resistance to EGFR-tyrosine kinase inhibitors. The antitumor effect was determined by using an 3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt (MTS) or colony formation assay. The protein expression was evaluated by using Western blotting. RESULTS: All 13 cell lines expressed EGFR protein, and siEGFR downregulated EGFR protein expression in all. The cell viability was suppressed by siEGFR in 6 of 8 EGFR-mutant cell lines (suppressed 57%-92% of control cells), including PC-9-GR1 and RPC-9. The NCI-H1650 and HCC827-ER harbored EGFR mutations but were not suppressed. Of note, PTEN (phosphatase and tensin homolog) was deleted in NCI-H1650, and c-MET was amplified in HCC827-ER. It was not suppressed in any of the EGFR wild-type cells except in the NCI-H411, in which EGFR is phosphorylated, which indicates its activation. CONCLUSIONS: Analysis of the results indicated that EGFR can be a therapeutic target in NSCLCs with EGFR activation. In contrast, targeting EGFR is not appropriate for tumors in which EGFR is not activated, even if EGFR is expressed.

DOI： 10.1016/j.cllc.2012.02.003

Induction chemoradiotherapy followed by surgical resection for clinical T3 or T4 locally advanced non-small cell lung cancer Reviewed International journal

Shien, K., Toyooka, S., Kiura, K., Matsuo, K., Soh, J., Yamane, M., Oto, T., Takemoto, M., Date, H., Miyoshi, S.

Ann Surg Oncol 19 ( 8 ) 2685 - 92 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

PURPOSE: To examine the usefulness of trimodality therapy in patients with clinical T3 or T4 (cT3-4) locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: Between 1997 and 2009, a total of 76 LA-NSCLC patients with cT3-4 underwent surgery. Among them, 36 patients underwent induction chemoradiotherapy with docetaxel and cisplatin plus concurrent radiation followed by surgery (IC group). The other 40 patients initially underwent surgery (IS group). The outcomes of the IC and IS groups were then investigated. To minimize possible biases caused by confounding treatment indications, we performed a retrospective cohort analysis by applying a propensity score (PS). Patients were divided into three groups according to PS tertiles, and comparisons between the IC and IS groups were made by PS tertile-stratified Cox proportional hazard models. RESULTS: For the entire cohort, which had a median follow-up duration of 48 months, the 3- and 5-year overall survival rates were 83.8 and 78.9%, respectively, in the IC group, versus 66.8 and 56.5%, respectively, in the IS group (P = 0.0092). After adjustments for potentially confounding variables, the IC group continued to have a significantly longer overall survival than the IS group (P = 0.0045). In addition, when the analysis was limited to 52 patients with cT3-4N0 or N1 disease, the IC group had a significantly longer overall survival than the IS group after adjustments for confounding variables (P = 0.019). CONCLUSIONS: Our study indicates that trimodality therapy is highly effective in patients with cT3-4 LA-NSCLC.

DOI： 10.1245/s10434-012-2302-x

Prognostic impact of cancer stem cell-related markers in non-small cell lung cancer patients treated with induction chemoradiotherapy Reviewed International journal

Shien, K., Toyooka, S., Ichimura, K., Soh, J., Furukawa, M., Maki, Y., Muraoka, T., Tanaka, N., Ueno, T., Asano, H., Tsukuda, K., Yamane, M., Oto, T., Kiura, K., Miyoshi, S.

Lung Cancer 77 ( 1 ) 162 - 7 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

The expression of several cancer stem cell (CSC)-related markers has been confirmed in non-small cell lung cancer (NSCLC). The aim of this study was to clarify the clinical role of CSC-related markers in patients with NSCLC undergoing induction chemoradiotherapy (CRT). Fifty patients with clinically diagnosed N2 or N3 NSCLC who underwent induction CRT with docetaxel and cisplatin concurrently with thoracic radiation followed by surgery were examined in this study. The expressions of CSC related markers (CD133, ALDH1, ABCG2, and Bmi-1) were examined using immunohistochemical staining in surgically resected specimens. Among the 50 patients, 20 patients had no residual tumor cells in the resected specimen when examined pathologically; CSC-related marker expressions and their correlation to survival were evaluated in the other 30 patients. After a median follow-up period of 72 months, the 5-year overall survival rate of the patients with CD133-positive or ALDH1-positive specimens was significantly worse than that of the patients with both CD133-negative and ALDH1-negative expressions (44.9% vs. 90.0%, respectively; P = 0.042). In a multivariate analysis, CD133 and ALDH1 negativity (P = 0.047) and cN2-3 single station metastasis (P = 0.03) were significant independent prognostic factors for prolonged survival. The expressions of CSC-related markers after CRT were significantly correlated with a poor prognosis in patients with NSCLC. The development of therapeutic strategies including adjuvant therapy that take CSC-related marker positivity into consideration is likely to be a key factor in further improvements of the prognosis of patients undergoing trimodality therapy.

DOI： 10.1016/j.lungcan.2012.02.006

MicroRNA miR-34b/c enhances cellular radiosensitivity of malignant pleural mesothelioma cells Reviewed International journal

Maki, Y., Asano, H., Toyooka, S., Soh, J., Kubo, T., Katsui, K., Ueno, T., Shien, K., Muraoka, T., Tanaka, N., Yamamoto, H., Tsukuda, K., Kishimoto, T., Kanazawa, S., Miyoshi, S.

Anticancer Res 32 ( 11 ) 4871 - 5 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：INT INST ANTICANCER RESEARCH

BACKGROUND: We previously reported that epigenetic silencing of microRNA-34b/c (miR-34b/c) plays an important role in the pathogenesis of malignant pleural mesothelioma (MPM). We examined the impact of miR-34b/c restoration on the radiosensitivity of MPM cells. MATERIALS AND METHODS: We established stable miR-34b/c and scramble transfectants of two MPM cell lines, H2052 and H28. We examined these transfectants by clonogenic survival assay, phosphorylated histone H2AX (γH2AX) foci assay, cell-cycle analysis, and western blotting. RESULTS: The clonogenic survival assay revealed that miR-34b/c radiosensitized MPM cells. γH2AX foci assay showed that DNA double-strand break repair was delayed in miR-34b/c transfectants. The proportion of sub-G(1) phase cells was increased in miR-34b/c transfectants after irradiation. miR-34b/c inhibited expression of cyclin-D1, cyclin-dependent kinase 4/6, B-cell lymphoma-2 (BCL-2) and increased cleaved poly (ADP-ribose) polymerase (cPARP) and cleaved caspase-3 after irradiation. CONCLUSION: Our results indicate that miR-34b/c enhances radiosensitivity by promoting radiation-induced apoptosis and suggested that miR-34b/c might be a useful therapeutic molecule to enhance radiotherapy in MPM.

Induction chemoradiotherapy is superior to induction chemotherapy for the survival of non-small-cell lung cancer patients with pathological mediastinal lymph node metastasis Reviewed International journal

Toyooka, S., Kiura, K., Shien, K., Katsui, K., Hotta, K., Kanazawa, S., Date, H., Miyoshi, S.

Interact Cardiovasc Thorac Surg 15 ( 6 ) 954 - 60 2012

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

OBJECTIVES: The purpose of this study was to compare the clinical outcomes of induction chemoradiotherapy and chemotherapy and to identify the prognostic factors for non-small-cell lung cancer patients with mediastinal lymph node metastasis who were treated with induction therapy. METHODS: Between August 1995 and December 2010, 50 non-small-cell lung cancer patients with pathological mediastinal lymph node metastasis were scheduled to receive induction therapy followed by surgery. Irinotecan plus cisplatin was used for induction chemotherapy from June 1995 to April 1999, and docetaxel plus cisplatin with concurrent radiation at a dose of 40-46 Gy has been used for induction chemoradiotherapy since May 1999. RESULTS: Thirty-five patients were treated with induction chemoradiotherapy and 15 were treated with induction chemotherapy. For the entire population, the 3-year and 5-year overall survival rates were 64.1 and 53.9%, respectively, and the 1-year and 2-year disease-free survival rates were 70.0 and 53.1%, respectively. Among the clinicopathological factors, the chemoradiotherapy group exhibited longer overall survival and disease-free survival than the chemotherapy group (overall survival, P = 0.0020; disease-free survival, P = 0.015). Pathological downstaging was also significantly associated with favorable overall survival (P = 0.0042) and disease-free survival (P = 0.021). A multivariate analysis showed that chemoradiotherapy (P = 0.0099) and pathological downstaging (P = 0.039) were independent prognostic factors. CONCLUSIONS: Our results indicated that induction chemoradiotherapy was superior to induction chemotherapy with regard to the outcome of non-small-cell lung cancer patients with mediastinal lymph node metastasis.

DOI： 10.1093/icvts/ivs412

Primary lung cancer surgery after curative chemoradiotherapy for esophageal cancer patients Reviewed International journal

Shien, K., Yamashita, M., Okazaki, M., Suehisa, H., Sawada, S., Miyoshi, S.

Interact Cardiovasc Thorac Surg 12 ( 6 ) 1002 - 6 2011

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

The safety and perioperative problems of primary lung cancer surgery after curative chemoradiotherapy (CRT) for thoracic esophageal cancer (EC) are controversial. We retrospectively evaluated six patients who had received curative CRT for EC from 2003 to 2009, in whom the lung nodule was identified as a primary lung cancer and who subsequently underwent pulmonary resection. The treatment for EC consisted of chemotherapy with cisplatin and 5-fluorouracil with concurrent curative thoracic radiotherapy (60 Gy). The median age at the surgery was 75 years (range 69-80 years). The median time from radiation to pulmonary resection was 26 months (range 7-70 months). All patients had a predicted postoperative forced expiratory volume in 1 s (FEV(1))% of >40% before lung surgery. The surgical difficulty involves mediastinal lymph node dissection following tissue fibrotic changes after thoracic radiation. Postoperative complications occurred in two patients, and included arrhythmia and empyema. The patient who developed empyema had a massive pericardial effusion after CRT and underwent pericardial fenestration at the time of pulmonary resection. There was no operative mortality. Lung cancer surgery after curative CRT for EC is feasible in carefully evaluated and selected patients.

DOI： 10.1510/icvts.2010.263509

Combination treatment with fulvestrant and various cytotoxic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) has a synergistic effect in estrogen receptor-positive breast cancer. Reviewed International journal

Ikeda, H., Taira, N., Nogami, T., Shien, K., Okada, M., Shien, T., Doihara, H., Miyoshi, S.

Cancer Sci 102 ( 11 ) 2038 - 42 2011

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Patients with estrogen receptor (ER)-positive breast cancers have a better prognosis than those with ER-negative breast cancers, but often have low sensitivity to chemotherapy and a limited survival benefit. We have previously shown a combination effect of taxanes and fulvestrant and suggested that this treatment may be useful for ER-positive breast cancer. In this study, we evaluated the effects of combinations of hormone drugs and chemotherapeutic agents. In vitro, the effects of combinations of five chemotherapeutic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) and three hormone drugs (fulvestrant, tamoxifen, and 4-hydroxytamoxifen) were examined in ER-positive breast cancer cell lines using CalcuSyn software. Changes in chemoresistant factors such as Bcl2, multidrug resistance-associated protein 1, and microtubule-associated protein tau were also examined after exposure of the cells to hormone drugs. In vivo, tumor sizes in mice were evaluated after treatment with docetaxel or doxorubicin alone, fulvestrant alone, and combinations of these agents. Combination treatment with fulvestrant and all five chemotherapeutic agents in vitro showed synergistic effects. In contrast, tamoxifen showed an antagonistic effect with all the chemotherapeutic agents. 4-Hydroxytamoxifen showed an antagonistic effect with doxorubicin and 5-fluorouracil, but a synergistic effect with taxanes and vinorelbine. Regarding chemoresistant factors, Bcl2 and microtubule-associated protein tau were downregulated by fulvestrant. In vivo, a combination of fulvestrant and docetaxel had a synergistic effect on tumor growth, but fulvestrant and doxorubicin did not show this effect. In conclusion, fulvestrant showed good compatibility with all the evaluated chemotherapeutic agents, and especially with docetaxel, in vitro and in vivo.

DOI： 10.1111/j.1349-7006.2011.02050.x

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