Abstract 679: ABI-231: A novel small molecule suppresses tumor growth and metastatic phenotypes of cervical cancer cells via targeting HPV E6 and E7

AbstractHuman papillomaviruses (HPV) are a major cause of malignancy worldwide, contributing to ~5% of all human cancers including almost all cases of cervical cancer and a growing number of ano-genital and oral cancers. HPV-induced malignancy is primarily driven by the viral oncogenes, E6 and E7, which manipulate host cellular pathways to increase cell proliferation and enhance cell survival, ultimately predisposing infected cells to malignant transformation. Consequently, a more detailed understanding of viral-host interactions in HPV-associated disease offers the potential to identify novel therapeutic targets. Here, we identify that the c-Jun N-terminal kinase (JNK) signalling pathway is activated in cervical disease and in cervical cancer. The HPV E6 oncogene induces JNK1/2 phosphorylation in a manner that requires the E6 PDZ binding motif. We show that blockade of JNK1/2 signalling using small molecule inhibitors, or knockdown of the canonical JNK substrate c-Jun, reduces cell proliferation and induces apoptosis in cervical cancer cells. We further demonstrate that this phenotype is at least partially driven by JNK-dependent activation of EGFR signalling via increased expression of EGFR and the EGFR ligands EGF and HB-EGF. JNK/c-Jun signalling promoted the invasive potential of cervical cancer cells and was required for the expression of the epithelial to mesenchymal transition (EMT)-associated transcription factor Slug and the mesenchymal marker Vimentin. Furthermore, JNK/c-Jun signalling is required for the constitutive expression of HPV E6 and E7, which are essential for cervical cancer cell growth and survival. Together, these data demonstrate a positive feedback loop between the EGFR signalling pathway and HPV E6/E7 expression, identifying a regulatory mechanism in which HPV drives EGFR signalling to promote proliferation, survival and EMT. Thus, our study has identified a novel therapeutic target that may be beneficial for the treatment of cervical cancer.

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Methyl jasmonate reduces the survival of cervical cancer cells and downregulates HPV E6 and E7, and survivin

Cancer Letters ◽

10.1016/j.canlet.2011.12.028 ◽

2012 ◽

Vol 319 (1) ◽

pp. 31-38 ◽

Cited By ~ 24

Author(s):

Elad Milrot ◽

Anna Jackman ◽

Tatiana Kniazhanski ◽

Pinhas Gonen ◽

Eliezer Flescher ◽

...

Keyword(s):

Cervical Cancer ◽

Methyl Jasmonate ◽

Cancer Cells ◽

Hpv E6 ◽

Cervical Cancer Cells ◽

E6 And E7

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Leukemia Inhibitory Factor Downregulates Human Papillomavirus-16 Oncogene Expression and Inhibits the Proliferation of Cervical Carcinoma Cells

Infectious Diseases in Obstetrics and Gynecology ◽

10.1155/2011/463081 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 9

Author(s):

Joseph M. Bay ◽

Bruce K. Patterson ◽

Nelson N. H. Teng

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Cancer Cells ◽

Leukemia Inhibitory Factor ◽

Inhibitory Factor ◽

Human Papillomavirus 16 ◽

Oncogene Expression ◽

Hpv E6 ◽

Cervical Cancer Cells ◽

E6 And E7

The constitutive proliferation and resistance to differentiation and apoptosis of neoplastic cervical cells depend on sustained expression of human papillomavirus oncogenes. Inhibition of these oncogenes is a goal for the prevention of progression of HPV-induced neoplasias to cervical cancer. SiHa cervical cancer cells were transfected with an HPV-16 promoter reporter construct and treated with leukemia inhibitory factor (LIF), a human cytokine of the interleukin 6 superfamily. SiHa and CaSki cervical cancer cells were also assessed for proliferation by MTT precipitation, programmed cell death by flow cytometry, and HPV E6 and E7 expression by real-time PCR. LIF-treated cervical cancer cells showed significantly reduced HPV LCR activation, reduced levels of E6 and E7 mRNA, and reduced proliferation. We report the novel use of LIF to inhibit viral oncogene expression in cervical cancer cells, with concomitant reduction in proliferation suggesting re-engagement of cell-cycle regulation.

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Suppression of HPV E6 and E7 expression by BAF53 depletion in cervical cancer cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2011.07.098 ◽

2011 ◽

Vol 412 (2) ◽

pp. 328-333 ◽

Cited By ~ 11

Author(s):

Kiwon Lee ◽

Ah-Young Lee ◽

Yunhee Kim Kwon ◽

Hyockman Kwon

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Hpv E6 ◽

Cervical Cancer Cells ◽

E6 And E7

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ERa-36 instead of ERa mediates the stimulatory effects of estrogen on the expression of viral oncogenes HPV E6/E7 and the malignant phenotypes in cervical cancer cells

Virus Research ◽

10.1016/j.virusres.2021.198602 ◽

2021 ◽

pp. 198602

Author(s):

Xiao Zhang ◽

Aowei Zhang ◽

Xi Zhang ◽

Shiyue Hu ◽

Zhenghao Bao ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Viral Oncogenes ◽

Hpv E6 ◽

Cervical Cancer Cells

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Upregulation of Long Non-Coding RNA Small Nucleolar RNA Host Gene 12 Contributes to Cell Growth and Invasion in Cervical Cancer by Acting as a Sponge for MiR-424-5p

Cellular Physiology and Biochemistry ◽

10.1159/000488045 ◽

2018 ◽

Vol 45 (5) ◽

pp. 2086-2094 ◽

Cited By ~ 33

Author(s):

Jing Dong ◽

Qing Wang ◽

Li Li ◽

Zhang Xiao-jin

Keyword(s):

Cervical Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Host Gene ◽

Migration And Invasion ◽

Small Nucleolar Rna ◽

Cervical Cancer Cells ◽

Cancer Tissues ◽

Nucleolar Rna

Background/Aims: Cervical cancer, which is one of the most aggressive cancers affecting females, has high rates of recurrence and mortality. Small nucleolar RNA host gene 12 (SNHG12) is known to promote the progression of several cancers; however, its exact effects and molecular mechanisms in cervical cancer remain unknown. Methods: Real-time quantitative PCR was used to determine the expression level of SNHG12 in cervical cancer tissues and cell lines. Loss-of-function assays were performed to examine the effect of SNHG12 on the proliferation, apoptosis, migration and invasion of cervical cancer cells in vitro and tumor growth in vivo. Luciferase experiments were employed to explore the interactions between SNHG12 and miR-424-5p. Results: SNHG12 was found to be abnormally elevated in human cervical cancer tissues compared with paired adjacent normal tissues. Moreover, high SNHG12 expression in tumor tissues was significantly correlated with vascular involvement, lymph node metastasis, advanced FIGO stage and poor prognosis. Furthermore, the knockdown of SNHG12 was found to inhibit proliferation, migration and invasion of cervical cancer cells in vitro, and silencing SNHG12 was shown to suppress tumor growth in a nude mouse model. Mechanistic studies showed that SNHG12 functioned as an endogenous sponge for miR-424-5p, thereby downregulating the expression of miR-424-5p in cervical cancer. Furthermore, the inhibition of miR-424-5p in SNHG12-depleted cells partially reversed the effects on cervical cancer cell apoptosis, adhesion and invasion. Conclusion: In summary, our findings suggest that the tumor-promoting role of SNHG12 is to function as a molecular sponge, which negatively regulates miR-424-5p. These findings may provide a potent therapeutic target for cervical cancer.

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