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Nuclear Receptor Expression and Function in Human Lung Cancer Pathogenesis.

Kim J, Sato M, Choi JW, Kim HW, Yeh BI, Larsen JE, Minna JD, Cha JH, Jeong Y - PLoS ONE (2015)

Bottom Line: Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs.In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner.Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea; Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea; Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea.

ABSTRACT
Lung cancer is caused by combinations of diverse genetic mutations. Here, to understand the relevance of nuclear receptors (NRs) in the oncogene-associated lung cancer pathogenesis, we investigated the expression profile of the entire 48 NR members by using QPCR analysis in a panel of human bronchial epithelial cells (HBECs) that included precancerous and tumorigenic HBECs harboring oncogenic K-rasV12 and/or p53 alterations. The analysis of the profile revealed that oncogenic alterations accompanied transcriptional changes in the expression of 19 NRs in precancerous HBECs and 15 NRs according to the malignant progression of HBECs. Amongst these, peroxisome proliferator-activated receptor gamma (PPARγ), a NR chosen as a proof-of-principle study, showed increased expression in precancerous HBECs, which was surprisingly reversed when these HBECs acquired full in vivo tumorigenicity. Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs. In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner. Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression. This suggests that ligand-mediated sumoylation of PPARγ plays an important role in lung cancer pathogenesis by modulating prostaglandin metabolism.

No MeSH data available.


Related in: MedlinePlus

Expression profile of the NR superfamily in immortalized HBEC panel.The QPCR assay was performed for mRNA expression of the entire NR superfamily in immortalized HBEC panel. (A) p53 knockdown-dependent expression. (B) Oncogenic K-rasV12-dependent expression. (C) p53 knockdown and K-rasV12-dependent expression. Note that HBEC-KT stands for HBEC cell lines immortalized by CDK4 plus hTERT; KTZ, KT plus control plasmid with zeocin selection marker; KTRL, KT plus oncogenic K-rasV12; KT53Z, KTZ plus p53 knock-down; KTRL53, KTRL plus p53 knockdown. Data represent the mean ± SD (n = 3). Asterisks show statistically significant points as evaluated by ANOVA. *P < 0.05, **P < 0.01 and ***P < 0.001 compared to HBEC-KT.
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pone.0134842.g002: Expression profile of the NR superfamily in immortalized HBEC panel.The QPCR assay was performed for mRNA expression of the entire NR superfamily in immortalized HBEC panel. (A) p53 knockdown-dependent expression. (B) Oncogenic K-rasV12-dependent expression. (C) p53 knockdown and K-rasV12-dependent expression. Note that HBEC-KT stands for HBEC cell lines immortalized by CDK4 plus hTERT; KTZ, KT plus control plasmid with zeocin selection marker; KTRL, KT plus oncogenic K-rasV12; KT53Z, KTZ plus p53 knock-down; KTRL53, KTRL plus p53 knockdown. Data represent the mean ± SD (n = 3). Asterisks show statistically significant points as evaluated by ANOVA. *P < 0.05, **P < 0.01 and ***P < 0.001 compared to HBEC-KT.

Mentions: Since we recently demonstrated that the expression pattern for the 48 NRs is a prognostic biomarker set as well as potentially being therapeutic targets for lung cancer [6–8], we wondered if any NRs are associated with lung cancer pathogenesis. Therefore, to explore whether the introduction of K-rasV12 and p53 oncogenic changes affected the expression of NRs in human lung bronchial epithelial cells, we first profiled the mRNA expression of all 48 members of the NR superfamily by QPCR in the isogenic HBEC panel that is oncogenically well-defined and composed of genetically identical bronchial epithelial cell lines (Fig 2 and S2 Fig). We found 31 out of 50 NRs (including PPARδ2 and PPARγ2, isoforms of PPARδ and PPARγ, respectively) to exhibit no differences in the isogenic panel (either had no expression or no change in expression) (S2 Fig). By contrast, 19 NRs showed distinct expression patterns across the isogenic HBEC panels, which fell into three different groups. The first group (p53 dependent) included two members, chicken ovalbumin upstream promoter-transcription factor (Coup-TF)α, estrogen receptor(ER)β, NRs showing a p53-dependent expression pattern (Fig 2A). The second group was represented by NRs with a K-rasV12-dependent expression pattern including Coup-TFβ, estrogen-related receptor (ERR)α, germ cell nuclear factor (GCNF), nerve growth factor induced gene B (NGFIB)3, neuron-derived orphan receptor 1 (NOR1), PPARα, PPARδ, PPARδ2, reverse-erb (Rev-erb)α, and retinoic acid-related orphan receptor (ROR)α, thyroid hormone receptor (TR)β (Fig 2B). The third group (K-rasV12 and p53 dependent) were ERα, hepatocyte nuclear factor 4 (HNF4)γ, nur-related factor 1 (NURR1), PPARγ, Retinoid acid receptor (RAR)β, RAR-related orphan receptor (ROR)β, which were NRs with a dual oncogene-dependent expression pattern (Fig 2C). In line with the results from our previous report in which NR expression was highly associated with lung cancer progression [7], this result supports the notion that subsets of NRs could also be involved in lung cancer pathogenesis induced by K-rasV12 overexpression and/or loss of p53 function.


Nuclear Receptor Expression and Function in Human Lung Cancer Pathogenesis.

Kim J, Sato M, Choi JW, Kim HW, Yeh BI, Larsen JE, Minna JD, Cha JH, Jeong Y - PLoS ONE (2015)

Expression profile of the NR superfamily in immortalized HBEC panel.The QPCR assay was performed for mRNA expression of the entire NR superfamily in immortalized HBEC panel. (A) p53 knockdown-dependent expression. (B) Oncogenic K-rasV12-dependent expression. (C) p53 knockdown and K-rasV12-dependent expression. Note that HBEC-KT stands for HBEC cell lines immortalized by CDK4 plus hTERT; KTZ, KT plus control plasmid with zeocin selection marker; KTRL, KT plus oncogenic K-rasV12; KT53Z, KTZ plus p53 knock-down; KTRL53, KTRL plus p53 knockdown. Data represent the mean ± SD (n = 3). Asterisks show statistically significant points as evaluated by ANOVA. *P < 0.05, **P < 0.01 and ***P < 0.001 compared to HBEC-KT.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4526668&req=5

pone.0134842.g002: Expression profile of the NR superfamily in immortalized HBEC panel.The QPCR assay was performed for mRNA expression of the entire NR superfamily in immortalized HBEC panel. (A) p53 knockdown-dependent expression. (B) Oncogenic K-rasV12-dependent expression. (C) p53 knockdown and K-rasV12-dependent expression. Note that HBEC-KT stands for HBEC cell lines immortalized by CDK4 plus hTERT; KTZ, KT plus control plasmid with zeocin selection marker; KTRL, KT plus oncogenic K-rasV12; KT53Z, KTZ plus p53 knock-down; KTRL53, KTRL plus p53 knockdown. Data represent the mean ± SD (n = 3). Asterisks show statistically significant points as evaluated by ANOVA. *P < 0.05, **P < 0.01 and ***P < 0.001 compared to HBEC-KT.
Mentions: Since we recently demonstrated that the expression pattern for the 48 NRs is a prognostic biomarker set as well as potentially being therapeutic targets for lung cancer [6–8], we wondered if any NRs are associated with lung cancer pathogenesis. Therefore, to explore whether the introduction of K-rasV12 and p53 oncogenic changes affected the expression of NRs in human lung bronchial epithelial cells, we first profiled the mRNA expression of all 48 members of the NR superfamily by QPCR in the isogenic HBEC panel that is oncogenically well-defined and composed of genetically identical bronchial epithelial cell lines (Fig 2 and S2 Fig). We found 31 out of 50 NRs (including PPARδ2 and PPARγ2, isoforms of PPARδ and PPARγ, respectively) to exhibit no differences in the isogenic panel (either had no expression or no change in expression) (S2 Fig). By contrast, 19 NRs showed distinct expression patterns across the isogenic HBEC panels, which fell into three different groups. The first group (p53 dependent) included two members, chicken ovalbumin upstream promoter-transcription factor (Coup-TF)α, estrogen receptor(ER)β, NRs showing a p53-dependent expression pattern (Fig 2A). The second group was represented by NRs with a K-rasV12-dependent expression pattern including Coup-TFβ, estrogen-related receptor (ERR)α, germ cell nuclear factor (GCNF), nerve growth factor induced gene B (NGFIB)3, neuron-derived orphan receptor 1 (NOR1), PPARα, PPARδ, PPARδ2, reverse-erb (Rev-erb)α, and retinoic acid-related orphan receptor (ROR)α, thyroid hormone receptor (TR)β (Fig 2B). The third group (K-rasV12 and p53 dependent) were ERα, hepatocyte nuclear factor 4 (HNF4)γ, nur-related factor 1 (NURR1), PPARγ, Retinoid acid receptor (RAR)β, RAR-related orphan receptor (ROR)β, which were NRs with a dual oncogene-dependent expression pattern (Fig 2C). In line with the results from our previous report in which NR expression was highly associated with lung cancer progression [7], this result supports the notion that subsets of NRs could also be involved in lung cancer pathogenesis induced by K-rasV12 overexpression and/or loss of p53 function.

Bottom Line: Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs.In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner.Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea; Institute of Lifestyle Medicine, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea; Nuclear Receptor Research Consortium, Wonju College of Medicine, Yonsei University, Wonju, Gangwon-do, Republic of Korea.

ABSTRACT
Lung cancer is caused by combinations of diverse genetic mutations. Here, to understand the relevance of nuclear receptors (NRs) in the oncogene-associated lung cancer pathogenesis, we investigated the expression profile of the entire 48 NR members by using QPCR analysis in a panel of human bronchial epithelial cells (HBECs) that included precancerous and tumorigenic HBECs harboring oncogenic K-rasV12 and/or p53 alterations. The analysis of the profile revealed that oncogenic alterations accompanied transcriptional changes in the expression of 19 NRs in precancerous HBECs and 15 NRs according to the malignant progression of HBECs. Amongst these, peroxisome proliferator-activated receptor gamma (PPARγ), a NR chosen as a proof-of-principle study, showed increased expression in precancerous HBECs, which was surprisingly reversed when these HBECs acquired full in vivo tumorigenicity. Notably, PPARγ activation by thiazolidinedione (TZD) treatment reversed the increased expression of pro-inflammatory cyclooxygenase 2 (COX2) in precancerous HBECs. In fully tumorigenic HBECs with inducible expression of PPARγ, TZD treatments inhibited tumor cell growth, clonogenecity, and cell migration in a PPARγ-sumoylation dependent manner. Mechanistically, the sumoylation of liganded-PPARγ decreased COX2 expression and increased 15-hydroxyprostaglandin dehydrogenase expression. This suggests that ligand-mediated sumoylation of PPARγ plays an important role in lung cancer pathogenesis by modulating prostaglandin metabolism.

No MeSH data available.


Related in: MedlinePlus