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The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression.

He C, Mao D, Hua G, Lv X, Chen X, Angeletti PC, Dong J, Remmenga SW, Rodabaugh KJ, Zhou J, Lambert PF, Yang P, Davis JS, Wang C - EMBO Mol Med (2015)

Bottom Line: The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP).Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer.Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer.

View Article: PubMed Central - PubMed

Affiliation: Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China.

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Effect of LATS1/2 on the growth of cancerous cervical cellsA Western blot analysis showed that LATS1/2 siRNAs successfully knocked down LATS1/2 and activated YAP in ME180 cells.B Knockdown of LATS1/2 promoted proliferation of ME180 cells. Each point represents the mean ± SEM of five independent experimental results. **P < 0.01 (P = 0.0020).C Representative images showing the anchorage-independent growth of ME180 with or without LATS1/2 knockdown (n = 5). Scale bar: 1 mm.D, E The concentrations of AREG in 2D (D) or 3D hanging-drop (E) culture medium from ME180 control and LATS1/2 knockdown cells. Each bar represents the mean ± SEM of five independent experimental results. Bars with different letters are significantly different from each other [CTRL vs. siLATS1/2 in (D), P = 0.0017; CTRL vs. siLATS1/2 in (E), P = 0.0045].Data information: Data in (B), (D), and (E) were analyzed for significance with unpaired t-test in GraphPad Prism 5 with Welch’s correction.
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fig16ev: Effect of LATS1/2 on the growth of cancerous cervical cellsA Western blot analysis showed that LATS1/2 siRNAs successfully knocked down LATS1/2 and activated YAP in ME180 cells.B Knockdown of LATS1/2 promoted proliferation of ME180 cells. Each point represents the mean ± SEM of five independent experimental results. **P < 0.01 (P = 0.0020).C Representative images showing the anchorage-independent growth of ME180 with or without LATS1/2 knockdown (n = 5). Scale bar: 1 mm.D, E The concentrations of AREG in 2D (D) or 3D hanging-drop (E) culture medium from ME180 control and LATS1/2 knockdown cells. Each bar represents the mean ± SEM of five independent experimental results. Bars with different letters are significantly different from each other [CTRL vs. siLATS1/2 in (D), P = 0.0017; CTRL vs. siLATS1/2 in (E), P = 0.0045].Data information: Data in (B), (D), and (E) were analyzed for significance with unpaired t-test in GraphPad Prism 5 with Welch’s correction.

Mentions: Treatment of confluent cervical cells with TGF-α and AREG resulted in a rapid and significant decrease in phosphorylation of LATS1, MOB1, and YAP (Figs6A and B and 7A, Appendix Figs S9, S10 and S13), suggesting that the Hippo pathway may involve in the YAP and EGFR signaling interaction. LATS1 and LATS2 are main components of the Hippo pathway and can directly phosphorylate YAP at Ser127. Knockdown of LATS1/2 in ME180 cells with LATS1/2 siRNAs activated YAP, which is indicated by a significant decrease in phospho-YAP (S127) (FigEV4A). Knockdown of LATS1/2 in ME180 cells also significantly increased cell proliferation and enhanced anchorage-independent cell growth (FigEV4B and C). The advantage of 3D culture, especially its high physiological relevance, has been reported (Friedrich et al, 2009). We found that knockdown of LATS1/2 significantly induced cell growth in the 3D culture system (Fig8A and B). Importantly, knockdown of LATS1/2 significantly increased the AREG secretion in both 2D and 3D culture (Fig EV4D and E). Consistent with 2D culture results, treatment of ME180 cells with AREG also significantly stimulated cell growth in the 3D culture system (Fig8C and E).


The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression.

He C, Mao D, Hua G, Lv X, Chen X, Angeletti PC, Dong J, Remmenga SW, Rodabaugh KJ, Zhou J, Lambert PF, Yang P, Davis JS, Wang C - EMBO Mol Med (2015)

Effect of LATS1/2 on the growth of cancerous cervical cellsA Western blot analysis showed that LATS1/2 siRNAs successfully knocked down LATS1/2 and activated YAP in ME180 cells.B Knockdown of LATS1/2 promoted proliferation of ME180 cells. Each point represents the mean ± SEM of five independent experimental results. **P < 0.01 (P = 0.0020).C Representative images showing the anchorage-independent growth of ME180 with or without LATS1/2 knockdown (n = 5). Scale bar: 1 mm.D, E The concentrations of AREG in 2D (D) or 3D hanging-drop (E) culture medium from ME180 control and LATS1/2 knockdown cells. Each bar represents the mean ± SEM of five independent experimental results. Bars with different letters are significantly different from each other [CTRL vs. siLATS1/2 in (D), P = 0.0017; CTRL vs. siLATS1/2 in (E), P = 0.0045].Data information: Data in (B), (D), and (E) were analyzed for significance with unpaired t-test in GraphPad Prism 5 with Welch’s correction.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4644376&req=5

fig16ev: Effect of LATS1/2 on the growth of cancerous cervical cellsA Western blot analysis showed that LATS1/2 siRNAs successfully knocked down LATS1/2 and activated YAP in ME180 cells.B Knockdown of LATS1/2 promoted proliferation of ME180 cells. Each point represents the mean ± SEM of five independent experimental results. **P < 0.01 (P = 0.0020).C Representative images showing the anchorage-independent growth of ME180 with or without LATS1/2 knockdown (n = 5). Scale bar: 1 mm.D, E The concentrations of AREG in 2D (D) or 3D hanging-drop (E) culture medium from ME180 control and LATS1/2 knockdown cells. Each bar represents the mean ± SEM of five independent experimental results. Bars with different letters are significantly different from each other [CTRL vs. siLATS1/2 in (D), P = 0.0017; CTRL vs. siLATS1/2 in (E), P = 0.0045].Data information: Data in (B), (D), and (E) were analyzed for significance with unpaired t-test in GraphPad Prism 5 with Welch’s correction.
Mentions: Treatment of confluent cervical cells with TGF-α and AREG resulted in a rapid and significant decrease in phosphorylation of LATS1, MOB1, and YAP (Figs6A and B and 7A, Appendix Figs S9, S10 and S13), suggesting that the Hippo pathway may involve in the YAP and EGFR signaling interaction. LATS1 and LATS2 are main components of the Hippo pathway and can directly phosphorylate YAP at Ser127. Knockdown of LATS1/2 in ME180 cells with LATS1/2 siRNAs activated YAP, which is indicated by a significant decrease in phospho-YAP (S127) (FigEV4A). Knockdown of LATS1/2 in ME180 cells also significantly increased cell proliferation and enhanced anchorage-independent cell growth (FigEV4B and C). The advantage of 3D culture, especially its high physiological relevance, has been reported (Friedrich et al, 2009). We found that knockdown of LATS1/2 significantly induced cell growth in the 3D culture system (Fig8A and B). Importantly, knockdown of LATS1/2 significantly increased the AREG secretion in both 2D and 3D culture (Fig EV4D and E). Consistent with 2D culture results, treatment of ME180 cells with AREG also significantly stimulated cell growth in the 3D culture system (Fig8C and E).

Bottom Line: The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP).Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer.Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer.

View Article: PubMed Central - PubMed

Affiliation: Olson Center for Women's Health, Department of Obstetrics & Gynecology, University of Nebraska Medical Center, Omaha, NE, USA College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China.

Show MeSH
Related in: MedlinePlus