Loss of the novel tumour suppressor and polarity gene Trim62 (Dear1) synergizes with oncogenic Ras in invasive lung cancer

Deregulation of cell polarity proteins has been linked to the processes of invasion and metastasis. TRIM62 is a regulator of cell polarity and a tumour suppressor in breast cancer. Here, we demonstrate that human non‐small cell lung cancer lesions show a step‐wise loss of TRIM62 levels during diseas...

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Published in	The Journal of pathology Vol. 234; no. 1; pp. 108 - 119
Main Authors	Quintás-Cardama, Alfonso, Post, Sean M, Solis, Luisa M, Xiong, Shunbin, Yang, Peirong, Chen, Nanyue, Wistuba, Ignacio I, Killary, Ann M, Lozano, Guillermina
Format	Journal Article
Language	English
Published	Chichester, UK John Wiley & Sons, Ltd 01.09.2014 Wiley Subscription Services, Inc
Subjects	Animals anoikis Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - pathology Cell Transformation, Neoplastic EMT Epithelial-Mesenchymal Transition Female Gene Expression Regulation, Neoplastic Genes, ras - genetics Humans Lung - metabolism Lung - pathology Lung cancer Lung Neoplasms - genetics Lung Neoplasms - pathology metastasis Mice Mice, Inbred BALB C Mice, Inbred C57BL mouse models Mutation Receptors, Angiotensin - genetics Receptors, Angiotensin - metabolism Receptors, Endothelin - genetics Receptors, Endothelin - metabolism Tripartite Motif Proteins Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism mouse models anoikis metastasis EMT
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Summary:	Deregulation of cell polarity proteins has been linked to the processes of invasion and metastasis. TRIM62 is a regulator of cell polarity and a tumour suppressor in breast cancer. Here, we demonstrate that human non‐small cell lung cancer lesions show a step‐wise loss of TRIM62 levels during disease progression, which was associated with poor clinical outcomes. To directly examine the role of Trim62 in development of lung cancer, we deleted Trim62 in a mutant K‐Ras mouse model of lung cancer. In this context, haploinsufficiency of Trim62 synergized with a K‐RasG12D mutation to promote invasiveness and disrupt three‐dimensional morphogenesis, both of which are associated with epithelial–mesenchymal transitions. Re‐expression of Trim62 reverted these phenotypes in tumour cell lines. Thus, Trim62 loss cooperates with K‐Ras mutation in tumourigenesis and metastasis in vivo, indicating that decreased levels of TRIM62 may play an important role in the evolution of lung cancer. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Bibliography:	ArticleID:PATH4385 ark:/67375/WNG-0F0X88TB-3 istex:B106335A07E9D8299967896E0779396C570227DC Appendix S1. Supporting InformationImmunostaining of lesions present in full lung sections of human non-small cell lung cancer specimens with a specific antibody against TRIM62. Areas of normal bronchial epithelium (NBE), atypical adenomatous hyperplasia (AAH), and carcinoma were scored based on intensity and extension of TRIM62 staining. TRIM62 expression in adenocarcinomas, squamous cell carcinomas, well-differentiated NSCLC and moderate- or poorly-differentiated NSCLC are shown in A). In each instance, the expression of TRIM62 is lost in a step-wise fashion as the histological grade of the lesions increases. B) Grading system for TRIM62. C) E-cadherin staining.Reduced Trim62 expression determined by RT-PCR analysis in Trim62 shRNA LKR13 cells compared with control cells (LKR13 parental cell line).K-ras+/LA1 (LKR13), Trim62+/−:K-ras+/LA1 (KDL444), and LKR13 Trim62 shRNA (Trim62sh5 and Trim62sh6) cells exhibit resistance to anoikis.Reduced Trim62 (black) and E-cadherin (orange) expression and increased vimentin (red) expression as assessed by RT-PCR analysis in tumours isolated from Trim62+/−:K-ras+/LA1 mice (KDL444 and KDL492). KDL444lung and KDL492lung indicate primary lung adenocarcinomas. KDL444met denotes renal lung cancer metastasis in mouse KDL444.Correlation between E-cadherin and Trim62 immunohistochemical expression in atypical adenomatous hyperplasia lesions (left panel) and in adenocarcinoma lesions (right panel). The very low expression of both E-cadherin and TRIM62 observed in adenocarcinomas is very tightly correlated (r = 0.81, p = 0.0003).Immunostaining of full lung sections obtained from Trim62+/−:K-ras+/LA1 mice with antibodies against Twist demonstrates high expression of this protein in lung tumours. A higher magnification (×400) is shown in the right panel. Immunohistochemical analysis revealed Twist expression in both cytoplasm and nuclei in lung cancer lesions with enhanced expression in the cytoplasm in most cases.Immunostaining of lung adenocarcinoma sections obtained from Trim62+/−:K-ras+/LA1 (first column), K-ras+/LA1 (second column), and Trim62+/− mice (fourth column) and of breast adenocarcinoma sections obtained from Trim62+/− mice (third column) with an antibody directed against CD44. High expression of CD44 is demonstrated in lesions from mice lacking Trim62 alleles but not in those obtained from mice that preserve both copies of Trim62 (ie K-ras+/LA1). 4×, 10×, and 40× magnifications are shown in the first, second, and third rows of images.Clinical characteristics of patients included in the tissue microarrayPatient characteristics of 72 patients assessed for TRIM62 expression as validation set No conflicts of interest were declared. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0022-3417 1096-9896 1096-9896
DOI:	10.1002/path.4385