Biological significance of promoter hypermethylation of p14/ARF gene: Relationships to p53 mutational status in Tunisian population with colorectal carcinoma

Chaar, Ines; Amara, Sameh; Elamine, Olfa Elhadj; Khiari, M.; Ounissi, Donia; Khalfallah, Tahar; Hmida, Abdelmajid Ben; Mzabi, Sabeh; Bouraoui, Saâdia

doi:10.1007/s13277-013-1198-9

Cited by 22 publications

(21 citation statements)

References 38 publications

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“…Furthermore, P14, P16, RASSF1A and PTEN are all TSGs; their functions have been investigated in a number of malignant tumors (28–30). These genes are frequently inactivated in numerous human malignancies including lung, breast and esophageal cancers (31–33).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-101 suppresses progression of lung cancer through the PTEN/AKT signaling pathway by targeting DNA methyltransferase 3A

et al. 2016

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It is well established that transcriptional silencing of critical tumor suppressor genes by DNA methylation is a fundamental process in the initiation of lung cancer. However, the involvement of microRNAs (miRNAs) in restoring abnormal DNA methylation patterns in lung cancer is not well understood. Therefore, and since miRNA-101 is complementary to the 3′-untranslated region of DNA methyltransferase 3A (DNMT3A), we investigated whether miRNA-101 could restore normal DNA methylation patterns in lung cancer cell lines. Bioinformatics has indicated that DNMT3A is a major target of miR-101. In addition, the overexpression of miR-101 downregulates DNMT3A. Using a methylation-specific polymerase chain reaction assay, we demonstrated that methylation of the phosphatase and tensin homolog (PTEN) promoter was reduced in A549 cells transfected with miR-101, but not in the transfected control. Furthermore, overexpression of miR-101 and silencing of DNMT3A suppressed lung cell proliferation and S/G2 transition, and increased apoptosis through the PTEN/AKT pathway in vitro. Furthermore, we observed the opposite phenomenon in A549 cells transfected with a miR-101 inhibitor. Subsequent investigation revealed that overexpression of miR-101 significantly inhibited the tumorigenicity of A549 cells in a nude mouse xenograft model. These results demonstrate that miR-101 affects lung cancer progression through the PTEN/AKT signaling pathway by targeting DNMT3A in lung cells, suggesting that miR-101 may be a novel potential therapeutic strategy in lung cancer treatment.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-101 suppresses progression of lung cancer through the PTEN/AKT signaling pathway by targeting DNA methyltransferase 3A

et al. 2016

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“…Extensive molecular analyses have revealed that colorectal carcinogenesis is characterized by a multi-step process of genetic and epigenetic alterations. p14 ARF -MDM2-p53 pathway is usually affected in colorectal carcinogenesis [7,8]. Studies reported that p14 ARF generally hypo-expresses in CRC.…”

Section: Introductionmentioning

confidence: 99%

“…Madoze-Gurpide J and colleagues measured that the protein level of p14 ARF in CRCs is 0.453 of that in non-tumor mucosal counterparts using a new antibody micro-array system [9]. Chaar I and colleagues found that 31 % of CRC patients did not express p14 ARF mRNA [7]. Although Pokemon has been proved to directly repress p14 ARF transcription in some tumors [10], whether Pokemon regulates p14 ARF expression in CRCs is yet known.…”

Section: Introductionmentioning

confidence: 99%

Pokemon enhances proliferation, cell cycle progression and anti-apoptosis activity of colorectal cancer independently of p14ARF–MDM2–p53 pathway

Zhao

Yao

et al. 2014

Med Oncol

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Pokemon has been showed to directly suppress p14(ARF) expression and also to overexpress in multiple cancers. However, p14(ARF)-MDM2-p53 pathway is usually aberrant in colorectal cancer (CRC). The aim is to confirm whether Pokemon plays a role in CRC and explore whether Pokemon works through p14(ARF)-MDM2-p53 pathway in CRC. Immunohistochemistry for Pokemon, p14(ARF) and Mtp53 protein was applied to 45 colorectal epitheliums (CREs), 42 colorectal adenomas (CRAs) and 66 CRCs. Pokemon was knocked down with RNAi technique in CRC cell line Lovo to detect mRNA expression of p14(ARF) with qRT-PCR, cell proliferation with CCK8 assay, and cell cycle and apoptosis with flowcytometry analysis. The protein expression rates were significantly higher in CRC (75.8%) than in CRE (22.2 %) or CRA (38.1%) for Pokemon and higher in CRC (53.0%) than in CRE (0) or CRA (4.8%) for Mtp53, but not significantly different in CRC (86.4 %) versus CRE (93.3%) or CRA (90.5 %) for p14(ARF). Higher expression rate of Pokemon was associated with lymph node metastasis and higher Duke's stage. After knockdown of Pokemon in Lovo cells, the mRNA level of p14(ARF) was not significantly changed, the cell proliferation ability was decreased by 20.6%, cell cycle was arrested by 55.7% in G0/G1 phase, and apoptosis rate was increased by 19.0%. Pokemon enhanced the oncogenesis of CRC by promoting proliferation, cell cycle progression and anti-apoptosis activity of CRC cells independently of p14(ARF)-MDM2-p53 pathway. This finding provided a novel idea for understanding and further studying the molecular mechanism of Pokemon on carcinogenesis of CRC.

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“…For CDKN2A ( p14) methylation, the study of Nilsson et al suggests a worse prognosis in TNM stages I–IV ( p = 0.036) [ 105 ], while the studies of Cleven et al and Chaar et al do not confirm these findings [ 73 , 99 ]. Subgroup analyses also do not show a statistically significant influence of CDKN2A ( p14) methylation on prognosis [ 73 ].…”

Section: Resultsmentioning

confidence: 99%

Prognostic DNA methylation markers for sporadic colorectal cancer: a systematic review

Draht¹,

Goudkade²,

Koch³

et al. 2018

Clin Epigenet

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BackgroundBiomarkers that can predict the prognosis of colorectal cancer (CRC) patients and that can stratify high-risk early stage patients from low-risk early stage patients are urgently needed for better management of CRC. During the last decades, a large variety of prognostic DNA methylation markers has been published in the literature. However, to date, none of these markers are used in clinical practice.MethodsTo obtain an overview of the number of published prognostic methylation markers for CRC, the number of markers that was validated independently, and the current level of evidence (LoE), we conducted a systematic review of PubMed, EMBASE, and MEDLINE. In addition, we scored studies based on the REMARK guidelines that were established in order to attain more transparency and complete reporting of prognostic biomarker studies. Eighty-three studies reporting on 123 methylation markers fulfilled the study entry criteria and were scored according to REMARK.ResultsSixty-three studies investigated single methylation markers, whereas 20 studies reported combinations of methylation markers. We observed substantial variation regarding the reporting of sample sizes and patient characteristics, statistical analyses, and methodology. The median (range) REMARK score for the studies was 10.7 points (4.5 to 17.5) out of a maximum of 20 possible points. The median REMARK score was lower in studies, which reported a p value below 0.05 versus those, which did not (p = 0.005). A borderline statistically significant association was observed between the reported p value of the survival analysis and the size of the study population (p = 0.051). Only 23 out of 123 markers (17%) were investigated in two or more study series. For 12 markers, and two multimarker panels, consistent results were reported in two or more study series. For four markers, the current LoE is level II, for all other markers, the LoE is lower.ConclusionThis systematic review reflects that adequate reporting according to REMARK and validation of prognostic methylation markers is absent in the majority of CRC methylation marker studies. However, this systematic review provides a comprehensive overview of published prognostic methylation markers for CRC and highlights the most promising markers that have been published in the last two decades.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0461-8) contains supplementary material, which is available to authorized users.

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Biological significance of promoter hypermethylation of p14/ARF gene: Relationships to p53 mutational status in Tunisian population with colorectal carcinoma

Cited by 22 publications

References 38 publications

MicroRNA-101 suppresses progression of lung cancer through the PTEN/AKT signaling pathway by targeting DNA methyltransferase 3A

MicroRNA-101 suppresses progression of lung cancer through the PTEN/AKT signaling pathway by targeting DNA methyltransferase 3A

Pokemon enhances proliferation, cell cycle progression and anti-apoptosis activity of colorectal cancer independently of p14ARF–MDM2–p53 pathway

Prognostic DNA methylation markers for sporadic colorectal cancer: a systematic review

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