Methylation of the long control region of HPV16 is related to the severity of cervical neoplasia

Dah Ching Ding, Ming Hsien Chiang, Hung Cheng Lai, Chao Agnes Hsiung, Chang Y. Hsieh, Tang Yuan Chu

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Objective: Oncogenic human papillomavirus (HPV) is the cause of cervical cancer. Hypermethylation of the CpG islands located at the long control region (LCR) of the HPV genome may regulate the expression of the major oncogenes E6 and E7, and may relate to cancer progression. The goal of the present study was to investigate the methylation patterns of CpG dinucleotides contained within the LCR of the HPV16 genome in a collection of clinical specimens comprising the full spectrum of cervical carcinogenesis. Study design: The status of LCR methylation was investigated in HPV16-infected cervical precancer and cancer cell lines, and in HPV16-infected low-grade squamous intraepithelial lesion of cervix (LSIL, n = 17), high-grade squamous intraepithelial lesion (HSIL, n = 21) and invasive squamous cell carcinoma (SCC, n = 15) by bisulfite sequencing. Results: Among the three CpG islands of HPV16 LCR, methylation was found in three in the CaSki cell, in two upstream ones in SiHa cell, and none in the precancerous Z172 cell. Reactivation of E6 gene expression upon demethylation by 5-aza-dC and TSA treatments was noted in CaSki cells. In HPV-infected cervical specimens, progressive methylation of HPV16 LCR was noted, with rates of 5.9%, 33.3% and 53.3% in LSIL, HSIL and SCC, respectively (P <0.01). A trend toward increasing density of CpG methylation was also noted. Topologically, more methylated sites were found at the E6/E7 promoter region in SCC, compared with LSIL and HSIL. Conclusion: The study disclosed downregulation of E6 gene transcription by LCR methylation in cervical cancer cells. Methylation of HPV 16 LCR is highly associated with severity of cervical neoplasm.

Original languageEnglish
Pages (from-to)215-220
Number of pages6
JournalEuropean Journal of Obstetrics Gynecology and Reproductive Biology
Volume147
Issue number2
DOIs
Publication statusPublished - Dec 2009
Externally publishedYes

Fingerprint

Methylation
Uterine Cervical Neoplasms
Neoplasms
CpG Islands
Specimen Handling
Human papillomavirus 16
Human Genome
Oncogenes
Genetic Promoter Regions
Squamous Cell Carcinoma
Carcinogenesis
Down-Regulation
Genome
Gene Expression
Cell Line
Genes
Squamous Intraepithelial Lesions of the Cervix

Keywords

  • Cervical cancer
  • Human papillomavirus
  • Long control region
  • Methylation

ASJC Scopus subject areas

  • Obstetrics and Gynaecology
  • Reproductive Medicine

Cite this

Methylation of the long control region of HPV16 is related to the severity of cervical neoplasia. / Ding, Dah Ching; Chiang, Ming Hsien; Lai, Hung Cheng; Hsiung, Chao Agnes; Hsieh, Chang Y.; Chu, Tang Yuan.

In: European Journal of Obstetrics Gynecology and Reproductive Biology, Vol. 147, No. 2, 12.2009, p. 215-220.

Research output: Contribution to journalArticle

Ding, Dah Ching ; Chiang, Ming Hsien ; Lai, Hung Cheng ; Hsiung, Chao Agnes ; Hsieh, Chang Y. ; Chu, Tang Yuan. / Methylation of the long control region of HPV16 is related to the severity of cervical neoplasia. In: European Journal of Obstetrics Gynecology and Reproductive Biology. 2009 ; Vol. 147, No. 2. pp. 215-220.
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abstract = "Objective: Oncogenic human papillomavirus (HPV) is the cause of cervical cancer. Hypermethylation of the CpG islands located at the long control region (LCR) of the HPV genome may regulate the expression of the major oncogenes E6 and E7, and may relate to cancer progression. The goal of the present study was to investigate the methylation patterns of CpG dinucleotides contained within the LCR of the HPV16 genome in a collection of clinical specimens comprising the full spectrum of cervical carcinogenesis. Study design: The status of LCR methylation was investigated in HPV16-infected cervical precancer and cancer cell lines, and in HPV16-infected low-grade squamous intraepithelial lesion of cervix (LSIL, n = 17), high-grade squamous intraepithelial lesion (HSIL, n = 21) and invasive squamous cell carcinoma (SCC, n = 15) by bisulfite sequencing. Results: Among the three CpG islands of HPV16 LCR, methylation was found in three in the CaSki cell, in two upstream ones in SiHa cell, and none in the precancerous Z172 cell. Reactivation of E6 gene expression upon demethylation by 5-aza-dC and TSA treatments was noted in CaSki cells. In HPV-infected cervical specimens, progressive methylation of HPV16 LCR was noted, with rates of 5.9{\%}, 33.3{\%} and 53.3{\%} in LSIL, HSIL and SCC, respectively (P <0.01). A trend toward increasing density of CpG methylation was also noted. Topologically, more methylated sites were found at the E6/E7 promoter region in SCC, compared with LSIL and HSIL. Conclusion: The study disclosed downregulation of E6 gene transcription by LCR methylation in cervical cancer cells. Methylation of HPV 16 LCR is highly associated with severity of cervical neoplasm.",
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T1 - Methylation of the long control region of HPV16 is related to the severity of cervical neoplasia

AU - Ding, Dah Ching

AU - Chiang, Ming Hsien

AU - Lai, Hung Cheng

AU - Hsiung, Chao Agnes

AU - Hsieh, Chang Y.

AU - Chu, Tang Yuan

PY - 2009/12

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N2 - Objective: Oncogenic human papillomavirus (HPV) is the cause of cervical cancer. Hypermethylation of the CpG islands located at the long control region (LCR) of the HPV genome may regulate the expression of the major oncogenes E6 and E7, and may relate to cancer progression. The goal of the present study was to investigate the methylation patterns of CpG dinucleotides contained within the LCR of the HPV16 genome in a collection of clinical specimens comprising the full spectrum of cervical carcinogenesis. Study design: The status of LCR methylation was investigated in HPV16-infected cervical precancer and cancer cell lines, and in HPV16-infected low-grade squamous intraepithelial lesion of cervix (LSIL, n = 17), high-grade squamous intraepithelial lesion (HSIL, n = 21) and invasive squamous cell carcinoma (SCC, n = 15) by bisulfite sequencing. Results: Among the three CpG islands of HPV16 LCR, methylation was found in three in the CaSki cell, in two upstream ones in SiHa cell, and none in the precancerous Z172 cell. Reactivation of E6 gene expression upon demethylation by 5-aza-dC and TSA treatments was noted in CaSki cells. In HPV-infected cervical specimens, progressive methylation of HPV16 LCR was noted, with rates of 5.9%, 33.3% and 53.3% in LSIL, HSIL and SCC, respectively (P <0.01). A trend toward increasing density of CpG methylation was also noted. Topologically, more methylated sites were found at the E6/E7 promoter region in SCC, compared with LSIL and HSIL. Conclusion: The study disclosed downregulation of E6 gene transcription by LCR methylation in cervical cancer cells. Methylation of HPV 16 LCR is highly associated with severity of cervical neoplasm.

AB - Objective: Oncogenic human papillomavirus (HPV) is the cause of cervical cancer. Hypermethylation of the CpG islands located at the long control region (LCR) of the HPV genome may regulate the expression of the major oncogenes E6 and E7, and may relate to cancer progression. The goal of the present study was to investigate the methylation patterns of CpG dinucleotides contained within the LCR of the HPV16 genome in a collection of clinical specimens comprising the full spectrum of cervical carcinogenesis. Study design: The status of LCR methylation was investigated in HPV16-infected cervical precancer and cancer cell lines, and in HPV16-infected low-grade squamous intraepithelial lesion of cervix (LSIL, n = 17), high-grade squamous intraepithelial lesion (HSIL, n = 21) and invasive squamous cell carcinoma (SCC, n = 15) by bisulfite sequencing. Results: Among the three CpG islands of HPV16 LCR, methylation was found in three in the CaSki cell, in two upstream ones in SiHa cell, and none in the precancerous Z172 cell. Reactivation of E6 gene expression upon demethylation by 5-aza-dC and TSA treatments was noted in CaSki cells. In HPV-infected cervical specimens, progressive methylation of HPV16 LCR was noted, with rates of 5.9%, 33.3% and 53.3% in LSIL, HSIL and SCC, respectively (P <0.01). A trend toward increasing density of CpG methylation was also noted. Topologically, more methylated sites were found at the E6/E7 promoter region in SCC, compared with LSIL and HSIL. Conclusion: The study disclosed downregulation of E6 gene transcription by LCR methylation in cervical cancer cells. Methylation of HPV 16 LCR is highly associated with severity of cervical neoplasm.

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KW - Methylation

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