Cyclin D1 and retinoblastoma susceptibility gene alterations in non-small cell lung cancer

Marchetti, Antonio; Doglioni, Claudio; Barbareschi, Mattia; Buttitta, Fiamma; Pellegrini, Silvia; Gaeta, P.; Rocca, Roberto La; Merlo, Giorgio R.; Chella, Antonio; Angeletti, Carlo Alberto; Palma, Paolo Dalla; Bevilacqua, Generoso

doi:10.1002/(sici)1097-0215(19980119)75:2<187::aid-ijc4>3.0.co;2-q

Cited by 50 publications

(16 citation statements)

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“…Kaplan-Meier analysis revealed a significantly shorter OS in “cyclin D1 high” (scores 6–12) NSCLC patients than in “cyclin D1 low” (0–4) patients ( p = 0.0113) (Supplementary Fig. S3B), which was consistent with previous reports 22, 23 . Additionally, cyclin D1 protein was increased in “FXR high” tumors (Fig.…”

Section: Resultssupporting

confidence: 91%

“…Notably, we observed a positive correlation between the expression of FXR and cyclin D1 in NSCLC samples, and the shortest OS was observed in patients with both high FXR and high cyclin D1 expression, indicating a potential mechanistic link. In agreement with our findings, CCND1 is a well-recognized oncogene, as well as a poor prognostic indicator, that is overexpressed in many cancers, including NSCLC 22, 23 . Here, we provide a new biomarker, FXR, which, in combination with cyclin D1, more effectively sub-stratifies NSCLC patients.…”

Section: Discussionsupporting

confidence: 92%

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Farnesoid X receptor, a novel proto-oncogene in non-small cell lung cancer, promotes tumor growth via directly transactivating CCND1

You

Liu

et al. 2017

Sci Rep

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Farnesoid X receptor (FXR), a nuclear receptor for maintaining bile acid homeostasis, has been recognized as a tumor suppressor in enterohepatic tissues. However, its expression and functional role in non-small cell lung cancer (NSCLC) remain unclear. We report that FXR is significantly increased in NSCLC and that it predicts poor clinical outcomes in NSCLC patients. FXR knockdown in NSCLC cells inhibited in vitro cell proliferation, blocked xenograft growth in nude mice, and delayed the G1/S transition of the cell cycle, whereas ectopic overexpression of FXR promoted NSCLC cell proliferation. Mechanistic analysis demonstrated that FXR could directly bind to an inverted repeat-0 sequence in the CCND1 promoter and activate its transcription. Cyclin D1 overexpression rescued NSCLC cells from the delayed G1/S transition and the impaired cell proliferation induced by FXR knockdown. Importantly, a positive correlation between the expression of FXR and cyclin D1 was confirmed in NSCLC samples, and patients with high expression of both FXR and cyclin D1 had the worst prognosis. In summary, our results suggest that FXR has oncogenic potential in NSCLC development, providing mechanistic insights that could be exploited for both prognostic and therapeutic purposes.

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Section: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 92%

Farnesoid X receptor, a novel proto-oncogene in non-small cell lung cancer, promotes tumor growth via directly transactivating CCND1

You

Liu

et al. 2017

Sci Rep

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“…The levels of p53, p16, and pRB protein expression in both whole sections and tissue microarrays from our tumour series are in general agreement with published results for lung tumours 6, 15–31. Differences in technique, tumour sample composition, and population profiles are likely to have contributed to wide variations in the levels reported for all of these proteins.…”

Section: Discussionsupporting

confidence: 90%

Expression of p53, pRB, and p16 in lung tumours: a validation study on tissue microarrays

Fielding

Watson

et al. 2003

The Journal of Pathology

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Tissue microarrays have been created from 326 lung tumours, including 173 squamous cell carcinomas (SCCs) and 132 adenocarcinomas (ADs). In order to evaluate the usefulness of this microarray series, the expression of p53, p16, and Rb proteins was compared by immunohistochemistry on both the tissue microarrays and the corresponding whole sections for all 326 tumours. The presence of replicate punches improved both the yield and the concordance of data relative to the whole section results, so that the consensus score from the replicates agreed with the whole section result in more than 90% of informative tumours. The large number of tumours in this series also allowed significant differences in protein expression patterns to be detected between SCC and AD, the major subtypes of non-small cell lung carcinoma (NSCLC). SCC had higher levels of p53 staining (67% vs 52% in AD) and substantially increased p16 loss (SCC 75%, AD 53%) combined with greater retention of pRB expression (SCC 86% vs 67% in AD). The strong inverse correlation between p16 and pRB seen in SCC was essentially absent in AD. This study represents the largest single immunohistochemical survey of protein expression for p53, p16, and RB in NSCLCs.

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“…Cyclin D1 is proposed to serve as an important switch in the regulation of continued cell-cycle progression and is often overexpressed in a variety of cancers (Marchetti et al , 1998; Lamb et al , 2003). To determine if PA28gamma repression by miR-7 affects cyclin D1 expression, we transfected A549 and H1299 cells with miR-7 or PA28gamma siRNA and evaluated cyclinD1 expression levels.…”

Section: Resultsmentioning

confidence: 99%

PA28gamma emerges as a novel functional target of tumour suppressor microRNA-7 in non-small-cell lung cancer

et al. 2013

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Background:MicroRNA-7 (miR-7) has been reported to be a tumour suppressor gene. However, whether it has a role in the growth of non-small-cell lung cancer (NSCLC) and what is its target involved in the tumour growth is still under investigation.Methods:NSCLC tissue sample, NSCLC cell lines and tissue microarray were investigated in this study. Total RNA, miRNA and protein were used for RT-PCR and western blot analysis. Immunohistochemistry was performed in tissues microarray. Cell culture and intervention experiments were performed in vitro and in vivo. Bioinformatics prediction, western blot and luciferase assay were identified the target of miR-7.Results:In this study, we found that the expression of miR-7 was significantly downregulated not only in NSCLC cell lines, but also in human NSCLC tissues compared with the matched adjacent tissues. Restoration of its expression through miR-7 mimics in A549 and H1299 NSCLC cells inhibited cell proliferation, colony formation, and cell-cycle progression in vitro. More importantly, the tumorigenicity in nude mice was reduced after administration of miR-7 in vivo. In advance, through bioinformatic analysis, luciferase assay and western blot, we identified a novel target of miR-7, PA28gamma (a proteasome activator) to be enrolled in the regulation with tumour. PA28gamma mRNA and protein levels are markedly upregulated in NSCLC cell lines and tumour samples, exhibiting a strong inverse relation with that of miR-7. In addition, knockdown of PA28gamma induced similar effects as overexpression of miR-7 in NSCLC cells. Furthermore, miR-7 overexpression or silencing of PA28gamma reduced the cyclinD1 expression at mRNA and protein level in NSCLC cell lines.Conclusion:All these findings strongly imply that the overexpression of PA28gamma resulted from miR-7 downexpression in NSCLC has an important role in promoting cancer cell progress and consequently results in NSCLC growth. Thus, strategies targeting PA28gamma and/or miR-7 may become promising molecular therapies in NSCLC treatment.

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Cyclin D1 and retinoblastoma susceptibility gene alterations in non-small cell lung cancer

Cited by 50 publications

References 20 publications

Farnesoid X receptor, a novel proto-oncogene in non-small cell lung cancer, promotes tumor growth via directly transactivating CCND1

Farnesoid X receptor, a novel proto-oncogene in non-small cell lung cancer, promotes tumor growth via directly transactivating CCND1

Expression of p53, pRB, and p16 in lung tumours: a validation study on tissue microarrays

PA28gamma emerges as a novel functional target of tumour suppressor microRNA-7 in non-small-cell lung cancer

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