HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor

Muñoz-Bello, J. Omar; Olmedo-Nieva, Leslie; Castro-Muñoz, Leonardo Josué; Manzo-Merino, Joaquín; Contreras‐Paredes, Adriana; González-Espinosa, Claudia; López-Saavedra, Alejandro; Lizano, Marcela

doi:10.3390/ijms19103153

Cited by 14 publications

(16 citation statements)

References 44 publications

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“…β-catenin is differentially expressed between CC and normal cervix, with multiple studies showing β-catenin expression in the nucleus and cytoplasm of CC cells compared to at the cell membrane in normal cervical tissue [110,111], suggesting enhanced β-catenin transcriptional activity in the former. HPV E6 and E7 proteins potentiate Wnt/β-catenin signaling by stabilizing β-catenin and by promoting β-catenin/TCF transcriptional activity [104,106,[112][113][114]. In transgenic mouse studies, combined overexpression of E7 and β-catenin produced higher rates of transformation to CC compared to overexpression of either E7 or β-catenin alone [18].…”

Section: Tumorigenesismentioning

confidence: 99%

Wnt Signaling in Gynecologic Malignancies

McMellen¹,

Woodruff²,

Corr

et al. 2020

IJMS

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Gynecologic malignancies, including ovarian cancer, endometrial cancer, and cervical cancer, affect hundreds of thousands of women worldwide every year. Wnt signaling, specifically Wnt/β-catenin signaling, has been found to play an essential role in many oncogenic processes in gynecologic malignancies, including tumorigenesis, metastasis, recurrence, and chemotherapy resistance. As such, the Wnt/β-catenin signaling pathway has the potential to be a target for effective treatment, improving patient outcomes. In this review, we discuss the evidence supporting the importance of the Wnt signaling pathways in the development, progression, and treatment of gynecologic malignancies.

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Section: Tumorigenesismentioning

confidence: 99%

Wnt Signaling in Gynecologic Malignancies

McMellen¹,

Woodruff²,

Corr

et al. 2020

IJMS

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“…All the findings demonstrated that MAGI3 inhibits CC cell migration and invasion by reducing bcatenin protein level; however, the precise molecular mechanism by how MAGI3 decreases b-catenin protein level still needs further investigation. HPV18 E6 was found to induce Wnt/b-catenin pathway activation and promote CC progression [35]; HPV18 E6 was also found to target MAGI3 for its degradation [32]. In this study, we proved that MAGI3 plays a crucial role in inhibiting Wnt/b-catenin signaling activation by reducing b-catenin protein level in CC cells (Fig.…”

Section: Discussionmentioning

confidence: 61%

Reduced MAGI3 level by HPV18E6 contributes to Wnt/β‐catenin signaling activation and cervical cancer progression

et al. 2021

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Human papillomavirus type 18 (HPV18) has high carcinogenic power in invasive cervical cancer (ICC) development. However, the underlying mechanism remains elusive. The carcinogenic properties of HPV18 require the PDZ-binding motif of its E6 oncoprotein (HPV18 E6) to degrade its target PSD95/Dlg/ZO-1 (PDZ) proteins. In this study, we demonstrated that the PDZ protein membrane-associated guanylate kinase, WW and PDZ domain containing 3 (MAGI3) inhibited the Wnt/b-catenin pathway, and subsequently cervical cancer (CC) cell migration and invasion, via decreasing b-catenin levels. By reducing MAGI3 protein levels, HPV18 E6 promoted CC cell migration and invasion through activation of Wnt/bcatenin signaling. Furthermore, HPV18 rather than HPV16 was preferentially associated with the downregulation of MAGI3 and activation of the Wnt/b-catenin pathway in CC. These findings shed light on the mechanism that gives HPV18 its high carcinogenic potential in CC progression.Cervical cancer (CC) is the fourth most prominent type of cancer in women [1]. Infection with high-risk types of human papillomaviruses (HR-HPVs) is the main cause for the transformation of normal cervical epithelium to cervical intraepithelial neoplasia (CIN) and progression to invasive cervical cancer (ICC) [2,3]. The 5-year overall survival for early-stage patients (stage I) of CC reaches 88%, and this percentage Abbreviations CC, cervical cancer; CIN, cervical intraepithelial neoplasia; CIS, carcinoma in situ; FDR, false discovery rate; GSEA, gene set enrichment analysis; HG-CIN, high-grade cervical intraepithelial neoplasia; HPV16, human papillomavirus type 16; HPV18, human papillomavirus type 18; HR-HPVs, high-risk types of human papillomaviruses; ICC, invasive cervical cancer; IHC, immunohistochemistry; MAGI3, membraneassociated guanylate kinase, WW and PDZ domain containing 3; NHERF1, Na + /H + exchanger regulatory factor 1; PBM, PDZ-binding motif; PDZ, PSD95/Dlg/ZO-1; TCGA, The Cancer Genome Atlas.

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“…Moreover, targets such as c-Myc and CyclinD1 are regulated directly at the translational level by AKT, so we should not limit the effect of β-catenin to oncogenic capabilities (36,37). Furthermore, while this work emphasizes the role of PI3K/AKT on presence and activity of ALDH, the possible participation of HPV oncoproteins must not to be excluded, since these have been associated to β-catenin activation and this could directly or indirectly explain ALDH regulation (38,39).…”

Section: Discussionmentioning

confidence: 96%

ALDHHIGH Population Is Regulated by the AKT/β-Catenin Pathway in a Cervical Cancer Model

et al. 2020

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ALDH is an enzyme involved in different cellular processes, including cancer. It has been shown that a cellular subpopulation with high ALDH activity (ALDH HIGH) within a tumor is related to functional capabilities such as stemness, chemoresistance, and tumorigenicity. However, few studies have focused on determining the mechanisms behind ALDH activity within the cells. Previously, our group reported that ALDH HIGH cells have higher tumorigenicity in Cervical Cancer (CC) cell lines. Based on this, we were interested to know the molecular mediators of the ALDH HIGH cells, specifically β-catenin, inasmuch as β-catenin is regulated through different pathways, such as Wnt signaling, and that it acts as a transcriptional co-activator involved in cancer progression. In this work, we show that the increase in ALDH HIGH cell percentage is reverted by β-catenin knockdown. Consistently, upon GSK3-β inactivation, a negative regulator of β-catenin, we observed an increase in ALDH HIGH cells. Additionally, we observed a low percentage of cells positive for Fzd receptor, suggesting that in our model there is a low capacity to respond to Wnt ligands. The analysis of ALDH HIGH cells in a sphere formation model demonstrated the active state of AKT. In accordance with this, impairment of AKT activity not only reduced β-catenin active state, but also the percentage of ALDH HIGH cells. This corroborates that AKT acts upstream of β-catenin, thus affecting the percentage of ALDH HIGH cells. In conclusion, our results show that ALDH HIGH cells are dependent on β-catenin, in spite of the Wnt pathway seems to be dispensable, while AKT emerges as central player supporting a mechanism in this important axis that is not yet well known but its analysis improves our understanding of ALDH activity on CC.

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HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor

Cited by 14 publications

References 44 publications

Wnt Signaling in Gynecologic Malignancies

Wnt Signaling in Gynecologic Malignancies

Reduced MAGI3 level by HPV18E6 contributes to Wnt/β‐catenin signaling activation and cervical cancer progression

ALDHHIGH Population Is Regulated by the AKT/β-Catenin Pathway in a Cervical Cancer Model

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