Human papillomavirus type 16 E6 suppresses microRNA-23b expression in human cervical cancer cells through DNA methylation of the host gene C9orf3

Yeung, Ching‐Hei; Tsang, Tsun Yee; Yau, WP; Kwok, Tim Tak

doi:10.18632/oncotarget.14555

Cited by 48 publications

(35 citation statements)

References 51 publications

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“…It has been demonstrated that miR-23b-3p is expressed at low levels in a variety of malignant tumors, including liver cancer [18], bladder cancer [19], cervical cancer [20], colorectal cancer [21], and prostate cancer [22]. Our preliminary experiments showed that PDAC tissues and cell lines also expressed low levels of miR-23b-3p.…”

Section: Discussionmentioning

confidence: 59%

Biological Effect and Mechanism of the miR-23b-3p/ANXA2 Axis in Pancreatic Ductal Adenocarcinoma

Wei

Dang

Feng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Accumulating evidence strongly suggests that microRNAs (miRNAs) modulate the expression of known tumor suppressor genes and oncogenes. In the present study, we found that the proliferation and invasion ability of pancreatic ductal adenocarcinoma (PDAC) cells were significantly suppressed by the overexpression of miR-23b-3p. In addition, there are miR-23b-3p binding sites in annexin A2 (ANXA2). Here, we investigated whether miR-23b-3p had an impact on the progression and metastasis of PDAC by targeting ANXA2. Methods: Cell proliferation, migration, and invasion, and cell cycle assays were performed to explore the effect of miR-23b-3p on various malignant phenotypes of pancreatic cancer cells. The size of tumors was observed following miR-23b-3p overexpression in an in vivo chick chorioallantoic membrane assay. Dual-luciferase reporter, quantitative real-time PCR, western blot, and immunohistochemical analyses were used to validate the relationship between miR-23b-3p and ANXA2 in vitro. Results: We observed that miR-23b-3p could bind specifically to the 3′ untranslated region of ANXA2 and inhibit its expression. MiR-23b-3p overexpression downregulated the expression of ANXA2 mRNA in PDAC cells and limited the size of tumors or even prevented tumor formation. In addition, there was a negative correlation between miR-23b-3p expression and ANXA2 protein expression in clinical specimens. Conclusion: MiR-23b-3p inhibits the development and progression of PDAC by regulating ANXA2 directly.

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Section: Discussionmentioning

confidence: 59%

Biological Effect and Mechanism of the miR-23b-3p/ANXA2 Axis in Pancreatic Ductal Adenocarcinoma

Wei

Dang

Feng

et al. 2018

Cell Physiol Biochem

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“…Both HPV oncoproteins E6 and E7 have previously been shown to regulate DNA methyltransferases (60)(61)(62), but only E6 has been shown to induce hypermethylation of the IFN-promoter in keratinocytes (15). The mechanism of E6-induced hypermethylation has not been determined.…”

Section: Discussionmentioning

confidence: 99%

Induction of Interferon Kappa in Human Papillomavirus 16 Infection by Transforming Growth Factor Beta-Induced Promoter Demethylation

Woodby

Songock

Scott

et al. 2018

J Virol

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Persistent high-risk human papillomavirus (HPV) infection is the major causal factor in cervical and other anogenital cancers. Because there are currently no therapeutics capable of preventing neoplastic progression of HPV infections, understanding the mechanisms of HPV-mediated persistence, including immune evasion, is a major research priority. The multifunctional growth factor transforming growth factor beta (TGFβ) has been shown to inhibit expression of early viral transcripts from cells harboring integrated HPV genomes or cells infected with retroviruses expressing HPV oncoproteins. However, the mechanism of TGFβ-induced inhibition has not been fully defined. In this study, we have observed a previously uncharacterized ability of TGFβ to repress the differentiation-induced upregulation of late HPV16 gene expression. In addition, interferon kappa (IFN-κ), a keratinocyte-specific, constitutively expressed cytokine suppressed by differentiation, can be transcriptionally induced by TGFβ1. TGFβ-mediated IFN-κ transcription only occurs in cells containing HPV16, and this is due to TGFβ1-mediated reversal of HPV-induced methylation of the IFN-κ promoter through active DNA demethylation mediated by thymine DNA glycosylase (TDG). This novel interaction between growth factor and innate immune signaling may shed light on the mechanisms of HPV persistence and how the virus manipulates both immune and growth factor signaling to promote its life cycle. Persistent infection by high-risk HPVs is the primary risk factor for development of HPV-induced cancers. Persistence involves viral evasion of the immune response, including the IFN response. HPV is also known to suppress TGFβ signaling, which inhibits viral gene expression. Here, we show that the TGFβ and IFN pathways are interrelated in the context of HPV16 infection through the upregulation of IFN-κ by TGFβ. The ability of TGFβ to induce IFN-κ promoter demethylation and transcriptional activation provides a new explanation for why HPV has evolved mechanisms to inhibit TGFβ in infected cells.

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“…A variety of hormones, growth factors and cytokines can stimulate Akt activation, thereby regulating cell growth, proliferation, motility, invasion, apoptosis and other processes (18). Studies have indicated that phosphorylation of AKT is increased in prostate, breast and cervical cancer cells (19)(20)(21). AKT was found to induce cell proliferation and survival in β cells, endothelial cells, cardiomyocytes and tumor cells (21,22).…”

Section: Introductionmentioning

confidence: 99%

HOXA5 inhibits the proliferation and induces the apoptosis of cervical cancer cells via regulation of protein kinase B and p27

Wang

2018

Oncol Rep

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Homeobox A5 (HOXA5) is a member of the homeobox gene (HOX) family, which plays an important role in the development of various malignant tumors. Here, we speculated that HOXA5 has an effect on cervical cancer development. In our study, we aimed to explore the role and molecular mechanism of HOXA5 in regards to the cell proliferation and apoptosis in cervical cancer. We found that expression levels of HOXA5 measured by RT-qPCR and western blot assays in cervical cancer cell lines and tissues were both significantly downregulated. We performed a gain-of-function experiment by the transfection with pcDNA.3.1-HOXA5 in ME-180 and HT-3 cells to overexpress HOXA5, and the caspase-3 activity measured by caspase-3 activity assay kit and cell apoptosis detected by flow cytometry were obviously promoted. Meanwhile, cell proliferation tested by BrdU assay, invasion determined by Transwell and cell viability tested by MTT were inhibited. Moreover, protein kinase B (AKT) was activated by incubation with SC79 (AKT activator; 1 µg/ml) after HOXA5 overexpression, and reversed the effect of HOXA5 overexpression on p27 expression. Additionally, significant elevation of AKT activation measured by western blot analysis abrogated the effect of HOXA5 on caspase-3 activity, cell apoptosis, proliferation, invasion and cell viability. Taken together, this study revealed that HOXA5 inhibits cervical cancer progression by regulating AKT/p27, proposing the potential role of HOXA5 in the prevention and treatment of cervical cancer.

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Human papillomavirus type 16 E6 suppresses microRNA-23b expression in human cervical cancer cells through DNA methylation of the host gene C9orf3

Cited by 48 publications

References 51 publications

Biological Effect and Mechanism of the miR-23b-3p/ANXA2 Axis in Pancreatic Ductal Adenocarcinoma

Biological Effect and Mechanism of the miR-23b-3p/ANXA2 Axis in Pancreatic Ductal Adenocarcinoma

Induction of Interferon Kappa in Human Papillomavirus 16 Infection by Transforming Growth Factor Beta-Induced Promoter Demethylation

HOXA5 inhibits the proliferation and induces the apoptosis of cervical cancer cells via regulation of protein kinase B and p27

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