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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor (LATS) Biosensor
Published on: September 13, 2018
LATS2 is a tumor suppressor gene of malignant mesothelioma
Hideki Murakami1, Tetsuya Mizuno, Tetsuo Taniguchi
1Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan.
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.
Insights
Inactivating the large tumor suppressor 2 (LATS2) gene, a component of the Hippo pathway, is common in malignant mesothelioma. Restoring LATS2 function inhibits cancer cell growth by deactivating YAP.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Malignant mesothelioma (MM) is an aggressive cancer linked to asbestos exposure.
- The Hippo signaling pathway plays a crucial role in tumor suppression.
Purpose of the Study:
- To investigate the role of the LATS2 gene and the Hippo pathway in malignant mesothelioma development.
- To identify genetic alterations in MM cell lines and tumors.
Main Methods:
- Genome-wide array-based comparative genomic hybridization (aCGH) was performed on 14 MM cell lines.
- LATS2 gene deletions and mutations were analyzed in 45 MM cell lines and tumors.
- LATS2 was transduced into MM cells to assess its functional impact.
- Immunohistochemistry was used to evaluate LATS2 expression in MM tumors.
Main Results:
- Homozygous deletions or mutations in LATS2 were found in 10 out of 45 MM cases.
- Transduction of LATS2 into MM cells inactivated YAP and inhibited cell proliferation.
- Low LATS2 expression was observed in 13 out of 45 MM tumors.
- NF2 mutations, affecting the upstream regulator Merlin, are common in MM.
Conclusions:
- Inactivation of LATS2 is a key mechanism for YAP activation in MM.
- Hippo pathway dysregulation, via LATS2 or NF2 inactivation, is frequent in malignant mesothelioma.
- Targeting the Hippo pathway may offer therapeutic strategies for MM.
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