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Y. Sekido
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ORAL 40 - Biology 1 (ID 154)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:C. Brambilla, R. Bueno
- Coordinates: 9/09/2015, 16:45 - 18:15, 702+704+706
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ORAL40.04 - Discussant for ORAL40.01, ORAL40.02, ORAL40.03 (ID 3466)
17:18 - 17:28 | Author(s): Y. Sekido
- Abstract
- Presentation
Abstract not provided
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-065 - Cyclin-Dependent kinase11 (CDK11) Is Crucial for Growth of Lung Cancer Cells (ID 877)
09:30 - 09:30 | Author(s): Y. Sekido
- Abstract
Background:
Cyclin dependent kinases (CDKs) are protein kinases that regulate cell growth and proliferation in cells. CDK11 belongs to transcriptional subfamilies of CDKs and has been reported to be crucial for survival of sarcoma and breast cancer cells. To examine its roles in lung cancer cells, we investigated the effect of CDK11 knockdown on non-small cell lung cancer (NSCLC) cell lines.
Methods:
17 NSCLC cell lines were used for expression analysis of CDK11. Among them, we used three lung cancer cell lines, H460, H1299 and H358 for functional analysis. Synthetic siRNAs were utilized to knockdown CDK11. mRNA and protein levels of CDK11 were evaluated by real-time PCR and western blotting, respectively. Changes in growth were examined by WST-1 proliferation assay and liquid and soft agar colony formation assays. Cell cycle and apoptosis were analyzed by FACS with propidium iodide staining.
Results:
Western blot analysis revealed that all of the 17 lung cancer cell lines expressed CDK11 mRNA and protein and that compared to a normal cell line, H460 expressed CDK11 at lower levels but H1299 and H358 expressed CDK11 at higher levels. CDK11 knockdown suppressed proliferation and anchorage-dependent and independent clonal growth in H460 and H1299 cell lines but not in H358. Induction of apoptosis was seen in H460 but not in the others.
Conclusion:
CDK11 knockdown suppressed proliferation and clonogenic growth in H460 and H1299 cells, and induced apoptosis in H460. These results suggest that inhibiting CDK11 may be an attractive target for the treatment of NSCLC.
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P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.08-001 - Hippo Pathway Dysregulation in Mesothelioma Cells (ID 1090)
09:30 - 09:30 | Author(s): Y. Sekido
- Abstract
Background:
Malignant mesothelioma (MM) is a highly aggressive tumor caused by asbestos exposure after a long latency. The neurofibromatosis type 2 (NF2) tumor suppressor gene is mutated in around 50% of MM cases, and encodes Merlin that regulates the Hippo tumor-suppressive signaling pathway. We previously reported occasional genetic or epigenetic alteration in the LATS2 and AJUBA genes in MMs, which encode components of the Hippo pathway. The LATS2 inactivation was shown to lead to constitutive activation of YAP, a prooncogenic protein and transcriptional coactivator, which enhances multiple cell cycle regulation genes including cyclin D1 (CCDN1). To further delineate the exact inactivation mechanism of this pathway and the roles of YAP in the development of MM, we established immortalized mesothelial cell lines and transduced YAP to determine whether or not YAP can confer the malignant phenotypes to these cells.
Methods:
Using retroviral transduction of HPV16 E6/E7 and hTERT genes, immortalized human omental mesothelial cell lines (HOMCs) were established. Three sublines (HOMC-B1, A4, and D4) with different morphologies were cloned by limiting dilution from the pool of immortalized cells. Retrovirus expression vectors of wild-type YAP (YAP[wt]) and mutant YAP (YAP[S127A]) were also synthesized. After retroviral infection of YAP expression vectors, transplantation of immortalized mesothelial cells was performed subcutaneously or intra-thoracically into nude mice.
Results:
We established immortalized mesothelial cell lines (HOMC) by transduction of HPV-E6/E7 and hTERT, and examined whether YAP activation induces malignant phenotypes in the cells. We found that transduction of both wild-type (YAP[wt]) and constitutively active-type (YAP[S127A]) YAP, but not other cell cycle-promoting genes including CCDN1 and FOXM1, enhanced HOMC-cell proliferation in vitro. We also tested whether or not YAP-transduced HOMC cells showed enhanced tumorigenicity in vivo after inoculation into nude mice subcutaneously or intrathoracically. We found that YAP[wt-] and YAP[S172A- ]induced tumors which displayed more aggressive phenotypes. Meanwhile, we also transduced YAP vectors into normal mesothelial cells but they were shown to be unable to immortalize them.
Conclusion:
YAP activation is frequently observed in MM cells. Although enforced expression of YAP[wt] or YAP[S127A] was insufficient to immortalize primary human mesothelial cells, the present study provides evidence for the crucial role of the disrupted Hippo pathway-activated YAP axis in the initiation of mesothelioma in vivo.
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P3.08-006 - NF2 Mutations in Malignant Pleural Mesothelioma Synchronous with Acoustic Neuroma: Disease-Causing Mutation or Chance Effect? (ID 2562)
09:30 - 09:30 | Author(s): Y. Sekido
- Abstract
Background:
Patients with neurofibromatosis type 2 (NF2) are predisposed to schwannomas and meningiomas. Somatic NF2 mutation has also been reported in patients with sporadic schwannomas and a variety of cancers. In particular, approximately 35–40% of patients with malignant pleural mesothelioma (MPM) carry inactivating mutations of NF2. In addition to NF2, BRCA1-associated protein-1 (BAP-1) has also been identified as a key genetic alteration in mesothelioma. Recently, a new familial cancer syndrome associated with germline mutations in BAP1 was proposed, which includes MPM, ocular melanoma, and other cancers. However, NF2 mutations do not usually cause mesothelioma synchronous with schwannoma. We here report two cases of MPM synchronous with vestibular schwannomas and analytical finding on NF2 mutations
Methods:
Case 1 was a 65-year-old man with epithelioid MPM. A unilateral acoustic neuroma was resected in 2010 because the patient experienced progressive hearing loss in the right ear since 2000. In April 2012, right pleural fluid was detected on chest X-ray and a thoracoscopical examination was performed. Epithelioid MPM was diagnosed pathologically. Case 2 was a 72-year-old man with epithelioid MPM synchronous with unilateral acoustic neurinoma. The patient presented with DOE and hearing loss in the left ear that had progressed over the past month. Chest X-ray showed pleural effusion, and a biopsied specimen with thoracoscopy revealed epithelioid MPM. Brain MRI and CT showed a mass that was highly suspected to be acoustic neurinoma between the left cerebellopontine angle and the opening of the internal acoustic meatus. We performed whole-exome sequencing on DNA in tumor tissue and blood and immunohistochemical analysis of NF2 gene encoding protein merlin.
Results:
Both patients were diagnosed with synchronous acoustic neurinoma and epithelioid MPM. NF2 gene mutations were identified in both tumors of MPM and acoustic neurinoma in Case 1. And in Case 2, diagnosis of acoustic neurinoma was depended on typical findings of brain MRI/CT, for which surgical resection was not performed because of advanced stage of MPM. Tumor tissue of MPM in Case 2 showed positive result of NF2 mutation. Both patients had a history of asbestos exposure.
Conclusion:
Although the role of NF2 mutation as a possible disease-causing mutation in MPM and synchronous occurrence with schwannoma remain unclear, both cases showed the possible role of NF2 mutation in asbestos-related neoplasm. We will show the pedigree of the patients’ families.
