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Background: WW domain binding protein-2 (WBP2) can function as a YAP/TAZ co-activator and play a vital role in promoting breast cancer progression. However, the expression and potential molecular mechanism of WBP2 in the context of lung cancer are not fully understood.
Methods: Expression and subcellular localization of WBP2 in clinical samples and in lung cancer cell lines were analyzed with respect to various clinical pathological parameters using Chi-square tests. We used a series of cell function experiments and tumor formation experiments in nude mice to verify the effect of WBP2 on tumor cell proliferation and invasion. Dual-directional regulation of WBP2 expression, immunoprecipitation, luciferase reporter assays, and quantitative PCR analyses were used to explore the regulatory mechanisms and identify associated molecular markers.
Results: We determined that WBP2 was highly expressed in lung cancer specimens and cell lines and that this expression was closely related to the pTNM stage, lymph node metastasis, and poor prognosis of patients. Additionally, gain and loss of function experiments revealed that WBP2 could significantly promote the proliferation and invasion of lung cancer cells both in vivo and in vitro. To elucidate the underlying molecular mechanism, we determined that wild-type WBP2 could competitively bind to the WW domain of WWC3 with LATS1 through its PPxY motifs to inhibit the formation of the WWC3-LATS1 complex, reduce the phosphorylation level of LATS1, and ultimately promote YAP nuclear translocation to suppress the activity of the Hippo pathway.
Conclusions: From the aspect of upstream molecules of Hippo signaling, WBP2 promotes the malignant phenotype of lung cancer cells in a unique manner that is not directly dependent upon YAP, thus providing a corresponding experimental basis for the development of targeted therapeutic drugs for lung cancer.
Keywords
WBP2, WWC3, LATS1, Hippo pathway, NSCLC, Invasion and metastasis
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 02 Dec, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cancer Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: WW domain binding protein-2 (WBP2) can function as a YAP/TAZ co-activator and play a vital role in promoting breast cancer progression. However, the expression and potential molecular mechanism of WBP2 in the context of lung cancer are not fully understood.
Methods: Expression and subcellular localization of WBP2 in clinical samples and in lung cancer cell lines were analyzed with respect to various clinical pathological parameters using Chi-square tests. We used a series of cell function experiments and tumor formation experiments in nude mice to verify the effect of WBP2 on tumor cell proliferation and invasion. Dual-directional regulation of WBP2 expression, immunoprecipitation, luciferase reporter assays, and quantitative PCR analyses were used to explore the regulatory mechanisms and identify associated molecular markers.
Results: We determined that WBP2 was highly expressed in lung cancer specimens and cell lines and that this expression was closely related to the pTNM stage, lymph node metastasis, and poor prognosis of patients. Additionally, gain and loss of function experiments revealed that WBP2 could significantly promote the proliferation and invasion of lung cancer cells both in vivo and in vitro. To elucidate the underlying molecular mechanism, we determined that wild-type WBP2 could competitively bind to the WW domain of WWC3 with LATS1 through its PPxY motifs to inhibit the formation of the WWC3-LATS1 complex, reduce the phosphorylation level of LATS1, and ultimately promote YAP nuclear translocation to suppress the activity of the Hippo pathway.
Conclusions: From the aspect of upstream molecules of Hippo signaling, WBP2 promotes the malignant phenotype of lung cancer cells in a unique manner that is not directly dependent upon YAP, thus providing a corresponding experimental basis for the development of targeted therapeutic drugs for lung cancer.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
This is a list of supplementary files associated with this preprint. Click to download.
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