title: Loss of the novel tumour suppressor and polarity gene Trim62 (Dear1) synergizes with oncogenic Ras in invasive lung cancer.
abstract: 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.
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Quintás-Cardama
authors.forename: Sean M
authors.initials: SM
authors.lastname: Post
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Solis
authors.forename: Shunbin
authors.initials: S
authors.lastname: Xiong
authors.forename: Peirong
authors.initials: P
authors.lastname: Yang
authors.forename: Nanyue
authors.initials: N
authors.lastname: Chen
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Ann M
authors.initials: AM
authors.lastname: Killary
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: C510877:Dear1 protein, mouse; D011945:Receptors, Angiotensin; D017466:Receptors, Endothelin; D000070584:Tripartite Motif Proteins; D025521:Tumor Suppressor Proteins; C583162:TRIM62 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: EMT; anoikis; metastasis; mouse models