Aberrant large tumor suppressor 2 (LATS2) gene expression correlates with EGFR mutation and survival in lung adenocarcinomas

Susan Y. Luo, Ko Yung Sit, Alan D L Sihoe, Wai Sing Suen, Wing Kuk Au, Ximing Tang, Edmond S K Ma, Wai Kong Chan, Ignacio I. Wistuba, John D. Minna, George S W Tsao, David C L Lam

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Abstract

Background: Large tumor suppressor 2 (LATS2) gene is a putative tumor suppressor gene with potential roles in regulation of cell proliferation and apoptosis in lung cancer. The aim of this study is to explore the association of aberrant LATS2 expression with EGFR mutation and survival in lung adenocarcinoma (AD), and the effects of LATS2 silencing in both lung AD cell lines. Methods: LATS2 mRNA and protein expression in resected lung AD were correlated with demographic characteristics, EGFR mutation and survival. LATS2-specific siRNA was transfected into four EGFR wild-type (WT) and three EGFR mutant AD cell lines and the changes in LATS2 expression and relevant signaling molecules before and after LATS2 knockdown were assayed. Results: Fifty resected lung AD were included (M:F = 23:27, smokers:non-smokers = 19:31, EGFR mutant:wild-type = 21:29) with LATS2 mRNA levels showed no significant difference between gender, age, smoking and pathological stages while LATS2 immunohistochemical staining on an independent set of 79 lung AD showed similar trend. LATS2 mRNA level was found to be a significant independent predictor for survival status (disease-free survival RR = 0.217; p= 0.003; Overall survival RR = 0.238; p= 0.036). siRNA-mediated suppression of LATS2 expression resulted in augmentation of ERK phosphorylation in EGFR wild-type AD cell lines with high basal LATS2 expression, discriminatory modulation of Akt signaling between EGFR wild-type and mutant cells, and induction of p53 accumulation in AD cell lines with low baseline p53 levels. Conclusions: LATS2 expression level is predictive of survival in patients with resected lung AD. LATS2 may modulate and contribute to tumor growth via different signaling pathways in EGFR mutant and wild-type tumors.

Original languageEnglish (US)
Pages (from-to)282-292
Number of pages11
JournalLung Cancer
Volume85
Issue number2
DOIs
StatePublished - 2014

Fingerprint

Tumor Suppressor Genes
Gene Expression
Mutation
Neoplasms
Survival
Cell Line
Adenocarcinoma
Adenocarcinoma of lung
Messenger RNA
Small Interfering RNA
Tumor Suppressor Proteins
Disease-Free Survival
Lung Neoplasms
Smoking
Phosphorylation
Cell Proliferation
Demography

Keywords

  • EGFR signaling
  • Gene expression
  • Gene silencing
  • Large tumor suppressor 2 gene
  • Lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Luo, S. Y., Sit, K. Y., Sihoe, A. D. L., Suen, W. S., Au, W. K., Tang, X., ... Lam, D. C. L. (2014). Aberrant large tumor suppressor 2 (LATS2) gene expression correlates with EGFR mutation and survival in lung adenocarcinomas. Lung Cancer, 85(2), 282-292. https://doi.org/10.1016/j.lungcan.2014.05.025

Aberrant large tumor suppressor 2 (LATS2) gene expression correlates with EGFR mutation and survival in lung adenocarcinomas. / Luo, Susan Y.; Sit, Ko Yung; Sihoe, Alan D L; Suen, Wai Sing; Au, Wing Kuk; Tang, Ximing; Ma, Edmond S K; Chan, Wai Kong; Wistuba, Ignacio I.; Minna, John D.; Tsao, George S W; Lam, David C L.

In: Lung Cancer, Vol. 85, No. 2, 2014, p. 282-292.

Research output: Contribution to journalArticle

Luo, SY, Sit, KY, Sihoe, ADL, Suen, WS, Au, WK, Tang, X, Ma, ESK, Chan, WK, Wistuba, II, Minna, JD, Tsao, GSW & Lam, DCL 2014, 'Aberrant large tumor suppressor 2 (LATS2) gene expression correlates with EGFR mutation and survival in lung adenocarcinomas', Lung Cancer, vol. 85, no. 2, pp. 282-292. https://doi.org/10.1016/j.lungcan.2014.05.025
Luo, Susan Y. ; Sit, Ko Yung ; Sihoe, Alan D L ; Suen, Wai Sing ; Au, Wing Kuk ; Tang, Ximing ; Ma, Edmond S K ; Chan, Wai Kong ; Wistuba, Ignacio I. ; Minna, John D. ; Tsao, George S W ; Lam, David C L. / Aberrant large tumor suppressor 2 (LATS2) gene expression correlates with EGFR mutation and survival in lung adenocarcinomas. In: Lung Cancer. 2014 ; Vol. 85, No. 2. pp. 282-292.
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abstract = "Background: Large tumor suppressor 2 (LATS2) gene is a putative tumor suppressor gene with potential roles in regulation of cell proliferation and apoptosis in lung cancer. The aim of this study is to explore the association of aberrant LATS2 expression with EGFR mutation and survival in lung adenocarcinoma (AD), and the effects of LATS2 silencing in both lung AD cell lines. Methods: LATS2 mRNA and protein expression in resected lung AD were correlated with demographic characteristics, EGFR mutation and survival. LATS2-specific siRNA was transfected into four EGFR wild-type (WT) and three EGFR mutant AD cell lines and the changes in LATS2 expression and relevant signaling molecules before and after LATS2 knockdown were assayed. Results: Fifty resected lung AD were included (M:F = 23:27, smokers:non-smokers = 19:31, EGFR mutant:wild-type = 21:29) with LATS2 mRNA levels showed no significant difference between gender, age, smoking and pathological stages while LATS2 immunohistochemical staining on an independent set of 79 lung AD showed similar trend. LATS2 mRNA level was found to be a significant independent predictor for survival status (disease-free survival RR = 0.217; p= 0.003; Overall survival RR = 0.238; p= 0.036). siRNA-mediated suppression of LATS2 expression resulted in augmentation of ERK phosphorylation in EGFR wild-type AD cell lines with high basal LATS2 expression, discriminatory modulation of Akt signaling between EGFR wild-type and mutant cells, and induction of p53 accumulation in AD cell lines with low baseline p53 levels. Conclusions: LATS2 expression level is predictive of survival in patients with resected lung AD. LATS2 may modulate and contribute to tumor growth via different signaling pathways in EGFR mutant and wild-type tumors.",
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T1 - Aberrant large tumor suppressor 2 (LATS2) gene expression correlates with EGFR mutation and survival in lung adenocarcinomas

AU - Luo, Susan Y.

AU - Sit, Ko Yung

AU - Sihoe, Alan D L

AU - Suen, Wai Sing

AU - Au, Wing Kuk

AU - Tang, Ximing

AU - Ma, Edmond S K

AU - Chan, Wai Kong

AU - Wistuba, Ignacio I.

AU - Minna, John D.

AU - Tsao, George S W

AU - Lam, David C L

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N2 - Background: Large tumor suppressor 2 (LATS2) gene is a putative tumor suppressor gene with potential roles in regulation of cell proliferation and apoptosis in lung cancer. The aim of this study is to explore the association of aberrant LATS2 expression with EGFR mutation and survival in lung adenocarcinoma (AD), and the effects of LATS2 silencing in both lung AD cell lines. Methods: LATS2 mRNA and protein expression in resected lung AD were correlated with demographic characteristics, EGFR mutation and survival. LATS2-specific siRNA was transfected into four EGFR wild-type (WT) and three EGFR mutant AD cell lines and the changes in LATS2 expression and relevant signaling molecules before and after LATS2 knockdown were assayed. Results: Fifty resected lung AD were included (M:F = 23:27, smokers:non-smokers = 19:31, EGFR mutant:wild-type = 21:29) with LATS2 mRNA levels showed no significant difference between gender, age, smoking and pathological stages while LATS2 immunohistochemical staining on an independent set of 79 lung AD showed similar trend. LATS2 mRNA level was found to be a significant independent predictor for survival status (disease-free survival RR = 0.217; p= 0.003; Overall survival RR = 0.238; p= 0.036). siRNA-mediated suppression of LATS2 expression resulted in augmentation of ERK phosphorylation in EGFR wild-type AD cell lines with high basal LATS2 expression, discriminatory modulation of Akt signaling between EGFR wild-type and mutant cells, and induction of p53 accumulation in AD cell lines with low baseline p53 levels. Conclusions: LATS2 expression level is predictive of survival in patients with resected lung AD. LATS2 may modulate and contribute to tumor growth via different signaling pathways in EGFR mutant and wild-type tumors.

AB - Background: Large tumor suppressor 2 (LATS2) gene is a putative tumor suppressor gene with potential roles in regulation of cell proliferation and apoptosis in lung cancer. The aim of this study is to explore the association of aberrant LATS2 expression with EGFR mutation and survival in lung adenocarcinoma (AD), and the effects of LATS2 silencing in both lung AD cell lines. Methods: LATS2 mRNA and protein expression in resected lung AD were correlated with demographic characteristics, EGFR mutation and survival. LATS2-specific siRNA was transfected into four EGFR wild-type (WT) and three EGFR mutant AD cell lines and the changes in LATS2 expression and relevant signaling molecules before and after LATS2 knockdown were assayed. Results: Fifty resected lung AD were included (M:F = 23:27, smokers:non-smokers = 19:31, EGFR mutant:wild-type = 21:29) with LATS2 mRNA levels showed no significant difference between gender, age, smoking and pathological stages while LATS2 immunohistochemical staining on an independent set of 79 lung AD showed similar trend. LATS2 mRNA level was found to be a significant independent predictor for survival status (disease-free survival RR = 0.217; p= 0.003; Overall survival RR = 0.238; p= 0.036). siRNA-mediated suppression of LATS2 expression resulted in augmentation of ERK phosphorylation in EGFR wild-type AD cell lines with high basal LATS2 expression, discriminatory modulation of Akt signaling between EGFR wild-type and mutant cells, and induction of p53 accumulation in AD cell lines with low baseline p53 levels. Conclusions: LATS2 expression level is predictive of survival in patients with resected lung AD. LATS2 may modulate and contribute to tumor growth via different signaling pathways in EGFR mutant and wild-type tumors.

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