Carbonic anhydrase 9 expression is associated with poor prognosis, tumor proliferation, and radiosensitivity of thymic carcinomas
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Yoichi Ohtaki1,2,3, Kimihiro Shimizu1,2, Reika Kawabata-Iwakawa4, Navchaa Gombodorj2, Bolag Altan5, Susumu Rokudai4, Arito Yamane4, Kyoichi Kaira5, Takehiko Yokobori6, Toshiteru Nagashima1,2, Kai Obayashi1,2, Seshiru Nakazawa1,2, Misaki Iijima1,2, Takayuki Kosaka1,2, Toshiki Yajima1,2, Akira Mogi1,2, Hiroyuki Kuwano2, Ken Shirabe2 and Masahiko Nishiyama3,4
1Division of General Thoracic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Maebashi, Gunma, Japan
2Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
3Education and Research Support Center, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
4Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
5Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
6Department of Innovative Cancer Immunotherapy, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
Kimihiro Shimizu, email: email@example.com
Keywords: thymic epithelial tumor; thymoma; thymic carcinoma; CA9; hypoxia
Received: May 25, 2018 Accepted: January 22, 2019 Published: February 12, 2019
Introduction: Thymic epithelial tumors (TETs) comprise several histologies of thymoma and thymic carcinomas (TCs), and TC frequently metastasizes and causes death. We therefore aimed here to identify key molecules closely related to prognosis and their biological roles in high-risk TETs, particularly TCs.
Results: RNA sequence analysis demonstrated that hypoxia-related genes were highly expressed in TETs. The expression of the hypoxia-related gene CA9 was noteworthy, particularly in TCs. Immunohistochemical analysis revealed that CA9 was expressed in 81.0% of TCs and 20.7% of all TET samples. CA9 expression was significantly associated with Masaoka stage, WHO classification, and recurrence-free survival after tumor resection (P = 0.005). The down-regulation of CA9 transcription in TC cell lines by small interfering RNAs significantly inhibited CA9 expression, which inhibited proliferation and increased sensitivity to irradiation.
Conclusions: CA9 expression may serve as a significant prognostic marker of TETs and therefore represents a potential target for the development of novel drugs and radiation-sensitizing therapy designed to improve the outcomes of patients with TCs.
Materials and Methods: We performed comprehensive transcriptome sequencing of 23 TETs and physiologic thymic specimens to identify genes highly and specifically expressed in high-risk TETs, particulary TCs. We performed immunohistochemical analysis of 179 consecutive surgically resected TETs to evaluate the significance of the association of protein expression with clinicopathological features and prognosis. The biological significance of the most promising prognostic marker was further studied using the TC cell lines, Ty-82 and MP57.
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