Increased miR-708 expression in NSCLC and its association with poor survival in lung adenocarcinoma from never smokers

Jin Sung Jang, Hyo Sung Jeon, Zhifu D Sun, Marie Christine Aubry, Hui Tang, Cheol Hong Park, Fariborz Rakhshan, Debra A. Schultz, Christopher P. Kolbert, Ruth Lupu, Jae Yong Park, Curtis C. Harris, Ping Yang, Jin Jen

Research output: Contribution to journalArticle

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Abstract

Purpose: miRNA plays an important role in human disease and cancer. We seek to investigate the expression status, clinical relevance, and functional role of miRNA in non-small cell lung cancer. Experimental Design:Weconducted miRNA expression profiling in matched lung adenocarcinoma and uninvolved lung using 56 pairs of fresh-frozen (FF) and 47 pairs of formalin-fixed, paraffin-embedded (FFPE) samples from never smokers. The most differentially expressed miRNA genes were evaluated by Cox analysis and log-rank test. Among the best candidate, miR-708 was further examined for differential expression in two independent cohorts. Functional significance of miR-708 expression in lung cancer was examined by identifying its candidate mRNA target and through manipulating its expression levels in cultured cells. Results: Among the 20 miRNAs most differentially expressed between tested tumor and normal samples, high expression level of miR-708 in the tumors was most strongly associated with an increased risk of death after adjustments for all clinically significant factors including age, sex, and tumor stage (FF cohort: HR, 1.90; 95% CI, 1.08-3.35; P=0.025 and FFPE cohort: HR, 1.93; 95% CI, 1.02-3.63; P=0.042). The transcript for TMEM88 gene has a miR-708 binding site in its 30 UTR and was significantly reduced in tumors high of miR-708. Forced miR-708 expression reduced TMEM88 transcript levels and increased the rate of cell proliferation, invasion, and migration in culture. Conclusions: miRNA-708 acts as an oncogene contributing to tumor growth and disease progression by directly downregulating TMEM88, a negative regulator of the Wnt signaling pathway in lung cancer.

Original languageEnglish (US)
Pages (from-to)3658-3667
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number13
DOIs
StatePublished - Jul 1 2012

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MicroRNAs
Survival
Neoplasms
Paraffin
Formaldehyde
Lung Neoplasms
Untranslated Regions
Wnt Signaling Pathway
Age Factors
Oncogenes
Non-Small Cell Lung Carcinoma
Genes
Cell Movement
Disease Progression
Adenocarcinoma of lung
Cultured Cells
Research Design
Down-Regulation
Binding Sites
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Increased miR-708 expression in NSCLC and its association with poor survival in lung adenocarcinoma from never smokers. / Jang, Jin Sung; Jeon, Hyo Sung; Sun, Zhifu D; Aubry, Marie Christine; Tang, Hui; Park, Cheol Hong; Rakhshan, Fariborz; Schultz, Debra A.; Kolbert, Christopher P.; Lupu, Ruth; Park, Jae Yong; Harris, Curtis C.; Yang, Ping; Jen, Jin.

In: Clinical Cancer Research, Vol. 18, No. 13, 01.07.2012, p. 3658-3667.

Research output: Contribution to journalArticle

Jang, JS, Jeon, HS, Sun, ZD, Aubry, MC, Tang, H, Park, CH, Rakhshan, F, Schultz, DA, Kolbert, CP, Lupu, R, Park, JY, Harris, CC, Yang, P & Jen, J 2012, 'Increased miR-708 expression in NSCLC and its association with poor survival in lung adenocarcinoma from never smokers', Clinical Cancer Research, vol. 18, no. 13, pp. 3658-3667. https://doi.org/10.1158/1078-0432.CCR-11-2857
Jang, Jin Sung ; Jeon, Hyo Sung ; Sun, Zhifu D ; Aubry, Marie Christine ; Tang, Hui ; Park, Cheol Hong ; Rakhshan, Fariborz ; Schultz, Debra A. ; Kolbert, Christopher P. ; Lupu, Ruth ; Park, Jae Yong ; Harris, Curtis C. ; Yang, Ping ; Jen, Jin. / Increased miR-708 expression in NSCLC and its association with poor survival in lung adenocarcinoma from never smokers. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 13. pp. 3658-3667.
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T1 - Increased miR-708 expression in NSCLC and its association with poor survival in lung adenocarcinoma from never smokers

AU - Jang, Jin Sung

AU - Jeon, Hyo Sung

AU - Sun, Zhifu D

AU - Aubry, Marie Christine

AU - Tang, Hui

AU - Park, Cheol Hong

AU - Rakhshan, Fariborz

AU - Schultz, Debra A.

AU - Kolbert, Christopher P.

AU - Lupu, Ruth

AU - Park, Jae Yong

AU - Harris, Curtis C.

AU - Yang, Ping

AU - Jen, Jin

PY - 2012/7/1

Y1 - 2012/7/1

N2 - Purpose: miRNA plays an important role in human disease and cancer. We seek to investigate the expression status, clinical relevance, and functional role of miRNA in non-small cell lung cancer. Experimental Design:Weconducted miRNA expression profiling in matched lung adenocarcinoma and uninvolved lung using 56 pairs of fresh-frozen (FF) and 47 pairs of formalin-fixed, paraffin-embedded (FFPE) samples from never smokers. The most differentially expressed miRNA genes were evaluated by Cox analysis and log-rank test. Among the best candidate, miR-708 was further examined for differential expression in two independent cohorts. Functional significance of miR-708 expression in lung cancer was examined by identifying its candidate mRNA target and through manipulating its expression levels in cultured cells. Results: Among the 20 miRNAs most differentially expressed between tested tumor and normal samples, high expression level of miR-708 in the tumors was most strongly associated with an increased risk of death after adjustments for all clinically significant factors including age, sex, and tumor stage (FF cohort: HR, 1.90; 95% CI, 1.08-3.35; P=0.025 and FFPE cohort: HR, 1.93; 95% CI, 1.02-3.63; P=0.042). The transcript for TMEM88 gene has a miR-708 binding site in its 30 UTR and was significantly reduced in tumors high of miR-708. Forced miR-708 expression reduced TMEM88 transcript levels and increased the rate of cell proliferation, invasion, and migration in culture. Conclusions: miRNA-708 acts as an oncogene contributing to tumor growth and disease progression by directly downregulating TMEM88, a negative regulator of the Wnt signaling pathway in lung cancer.

AB - Purpose: miRNA plays an important role in human disease and cancer. We seek to investigate the expression status, clinical relevance, and functional role of miRNA in non-small cell lung cancer. Experimental Design:Weconducted miRNA expression profiling in matched lung adenocarcinoma and uninvolved lung using 56 pairs of fresh-frozen (FF) and 47 pairs of formalin-fixed, paraffin-embedded (FFPE) samples from never smokers. The most differentially expressed miRNA genes were evaluated by Cox analysis and log-rank test. Among the best candidate, miR-708 was further examined for differential expression in two independent cohorts. Functional significance of miR-708 expression in lung cancer was examined by identifying its candidate mRNA target and through manipulating its expression levels in cultured cells. Results: Among the 20 miRNAs most differentially expressed between tested tumor and normal samples, high expression level of miR-708 in the tumors was most strongly associated with an increased risk of death after adjustments for all clinically significant factors including age, sex, and tumor stage (FF cohort: HR, 1.90; 95% CI, 1.08-3.35; P=0.025 and FFPE cohort: HR, 1.93; 95% CI, 1.02-3.63; P=0.042). The transcript for TMEM88 gene has a miR-708 binding site in its 30 UTR and was significantly reduced in tumors high of miR-708. Forced miR-708 expression reduced TMEM88 transcript levels and increased the rate of cell proliferation, invasion, and migration in culture. Conclusions: miRNA-708 acts as an oncogene contributing to tumor growth and disease progression by directly downregulating TMEM88, a negative regulator of the Wnt signaling pathway in lung cancer.

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