LATS2 Is a Tumor Suppressor Gene of Malignant Mesothelioma

1. Hideki Murakami1,
2. Tetsuya Mizuno1,4,
3. Tetsuo Taniguchi1,4,
4. Makiko Fujii1,
5. Futoshi Ishiguro1,4,
6. Takayuki Fukui2,
7. Shinya Akatsuka6,
8. Yoshitsugu Horio3,
9. Toyoaki Hida3,
10. Yutaka Kondo1,
11. Shinya Toyokuni6,
12. Hirotaka Osada1,5, and
13. Yoshitaka Sekido1,5

+ Author Affiliations

1. Authors' Affiliations:¹Division of Molecular Oncology, Aichi Cancer Center Research Institute; Departments of ²Thoracic Surgery and ³Thoracic Oncology, Aichi Cancer Center Hospital; Departments of ⁴Cardio-Thoracic Surgery and ⁵Cancer Genetics, Program in Function Construction Medicine, and ⁶Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan

1. Corresponding Author:
   Yoshitaka Sekido, Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi 464-8681, Japan. Phone: 81-52-764-2983; Fax: 81-52-764-2993. E-mail: ysekido@aichi-cc.jp

Abstract

Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive activation of YAP, which induces deregulation of MM cell proliferation

sourse : http://cancerres.aacrjournals.org/content/71/3/873.short