Dataset Information

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.

SUBMITTER: Quintas-Cardama A

PROVIDER: S-EPMC4138305 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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

Quintás-Cardama Alfonso A Post Sean M SM Solis Luisa M LM Xiong Shunbin S Yang Peirong P Chen Nanyue N Wistuba Ignacio I II Killary Ann M AM Lozano Guillermina G

The Journal of pathology 20140716 1

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. I ...[more]

PMID: 24890125

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Project description:BackgroundEpithelial neoplasias are associated with alterations in cell polarity and excessive cell proliferation, yet how these neoplastic properties are related to one another is still poorly understood. The study of Drosophila genes that function as neoplastic tumor suppressors by regulating both of these properties has significant potential to clarify this relationship.ResultsHere we show in Drosophila that loss of Scribbled (Scrib), a cell polarity regulator and neoplastic tumor suppressor, results in impaired Hippo pathway signaling in the epithelial tissues of both the eye and wing imaginal disc. scrib mutant tissue overgrowth, but not the loss of cell polarity, is dependent upon defective Hippo signaling and can be rescued by knockdown of either the TEAD/TEF family transcription factor Scalloped or the transcriptional coactivator Yorkie in the eye disc, or reducing levels of Yorkie in the wing disc. Furthermore, loss of Scrib sensitizes tissue to transformation by oncogenic Ras-Raf signaling, and Yorkie-Scalloped activity is required to promote this cooperative tumor overgrowth. The inhibition of Hippo signaling in scrib mutant eye disc clones is not dependent upon JNK activity, but can be significantly rescued by reducing aPKC kinase activity, and ectopic aPKC activity is sufficient to impair Hippo signaling in the eye disc, even when JNK signaling is blocked. In contrast, warts mutant overgrowth does not require aPKC activity. Moreover, reducing endogenous levels of aPKC or increasing Scrib or Lethal giant larvae levels does not promote increased Hippo signaling, suggesting that aPKC activity is not normally rate limiting for Hippo pathway activity. Epistasis experiments suggest that Hippo pathway inhibition in scrib mutants occurs, at least in part, downstream or in parallel to both the Expanded and Fat arms of Hippo pathway regulation.ConclusionsLoss of Scrib promotes Yorkie/Scalloped-dependent epithelial tissue overgrowth, and this is also important for driving cooperative tumor overgrowth with oncogenic Ras-Raf signaling. Whether this is also the case in human cancers now warrants investigation since the cell polarity function of Scrib and its capacity to restrain oncogene-mediated transformation, as well as the tissue growth control function of the Hippo pathway, are conserved in mammals.

Dataset Information

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

Publications

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

Similar Datasets

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