scholarly journals EGFR Regulates the Hippo pathway by promoting the tyrosine phosphorylation of MOB1

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Toshinori Ando ◽  
Nadia Arang ◽  
Zhiyong Wang ◽  
Daniela Elena Costea ◽  
Xiaodong Feng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Squamous Cell Carcinoma ◽  
Hippo Pathway ◽  
Cancer Recurrence ◽  
Treatment Resistance ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Egfr Inhibitor ◽  
Growth Promoting ◽  
The Hippo Pathway

AbstractThe Hippo pathway is frequently dysregulated in cancer, leading to the unrestrained activity of its downstream targets, YAP/TAZ, and aberrant tumor growth. However, the precise mechanisms leading to YAP/TAZ activation in most cancers is still poorly understood. Analysis of large tissue collections revealed YAP activation in most head and neck squamous cell carcinoma (HNSCC), but only 29.8% of HNSCC cases present genetic alterations in the FAT1 tumor suppressor gene that may underlie persistent YAP signaling. EGFR is overexpressed in HNSCC and many other cancers, but whether EGFR controls YAP activation is still poorly understood. Here, we discover that EGFR activates YAP/TAZ in HNSCC cells, but independently of its typical signaling targets, including PI3K. Mechanistically, we find that EGFR promotes the phosphorylation of MOB1, a core Hippo pathway component, and the inactivation of LATS1/2 independently of MST1/2. Transcriptomic analysis reveals that erlotinib, a clinical EGFR inhibitor, inactivates YAP/TAZ. Remarkably, loss of LATS1/2, resulting in aberrant YAP/TAZ activity, confers erlotinib resistance on HNSCC and lung cancer cells. Our findings suggest that EGFR-YAP/TAZ signaling plays a growth-promoting role in cancers harboring EGFR alterations, and that inhibition of YAP/TAZ in combination with EGFR might be beneficial to prevent treatment resistance and cancer recurrence.

scholarly journals MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1

2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Ching-Wen Lin ◽  
Yih-Leong Chang ◽  
Yu-Chiuan Chang ◽  
Jau-Chen Lin ◽  
Chun-Chi Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Metastasis ◽  
Hippo Pathway ◽  
Multiple Targets ◽  
Lung Cancer Metastasis ◽  
The Hippo Pathway

scholarly journals The Hippo pathway transcriptional co-activator, YAP, confers resistance to cisplatin in human oral squamous cell carcinoma

2015 ◽  
Vol 46 (6) ◽  
pp. 2364-2370 ◽  
Author(s):  
KYOHEI YOSHIKAWA ◽  
KAZUMA NOGUCHI ◽  
YOSHIRO NAKANO ◽  
MICHIYO YAMAMURA ◽  
KAZUKI TAKAOKA ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Hippo Pathway ◽  
The Hippo Pathway

scholarly journals Evaluation of Hippo Pathway and CD133 in Radiation Resistance in Small-Cell Lung Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Kui Yang ◽  
Yang Zhao ◽  
Yonghao Du ◽  
Ruixiang Tang
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Radiation Resistance ◽  
Hippo Pathway ◽  
Small Cell ◽  
Cell Counting ◽  
Disease Stage ◽  
Small Cell Lung ◽  
The Hippo Pathway

Although the Hippo pathway and CD133 have been reported to play pertinent roles in a variety of cancer, knowledge about their contribution to radiation resistance in small-cell lung cancer (SCLC) is limited. In this first-of-a-kind study, we have reported the expression of key Hippo pathway proteins in SCLC patients by immunohistochemical staining. We assessed the involvement of yes-associated protein 1 (YAP1) in radiation resistance by Cell Counting Kit-8 (CCK-8) and flow cytometry. In addition, we analysed the impact of CD133 on radiotherapy for SCLC. The mammalian Ste20-like serine/threonine kinase 2(MST2), pMST2, and pYAP1 in the Hippo pathway were not significantly associated with the disease stage and survival time in patients with SCLC. However, the pYAP1 expression showed some significance in the “YAP/TAZ subgroup” of SCLC patients. The proportion of CD133 in the SCLC cells was controlled by the YAP1 expression. The CD133 and YAP1 levels were significantly correlation with each other in tissues of SCLC patients. We sorted and isolated the CD133+ and CD133−cells in H69 and found that the cell surface glycoprotein may be associated with the radiation resistance of SCLC.In summary, we have firstly reported the expression of key Hippo pathway proteins in SCLC patients. Furthermore, we also identified that CD133 may be controlled by the expression of YAP1 in the Hippo pathway and that CD133 may be associated with the radiation resistance of SCLC.

scholarly journals The Predictive Values of Advanced Non-Small Cell Lung Cancer Patients Harboring Uncommon EGFR Mutations—The Mutation Patterns, Use of Different Generations of EGFR-TKIs, and Concurrent Genetic Alterations

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiarong Tan ◽  
Chengping Hu ◽  
Pengbo Deng ◽  
Rongjun Wan ◽  
Liming Cao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Small Cell Lung Cancer ◽  
Tumor Suppressor Gene ◽  
Cell Lung Cancer ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Gene Alterations

IntroductionEpidermal growth factor receptor (EGFR) 19del and L858R mutation are known as “common mutations” in non-small cell lung cancer (NSCLC) and predict sensitivities to EGFR tyrosine kinase inhibitors (TKIs), whereas 20ins and T790M mutations confer drug-resistance to EGFR-TKIs. The role of the remaining uncommon EGFR mutations remains elusive.MethodsWe retrospectively screened a group of NSCLC patients with uncommon EGFR mutations other than 20ins and T790M. The mutation patterns, use of different generations of EGFR-TKIs, and concurrent genetic alterations were analyzed. Meanwhile, a cohort of patients with single 19del or L858R were included for comparison.ResultsA total of 180/1,300 (13.8%) patients were identified. There were 102 patients with advanced or recurrent NSCLC that received first-line therapy of gefitinib/erlotinib/icotinib and afatinib and were eligible for analysis. The therapeutic outcomes among patients with common mutations (EGFRcm, n = 97), uncommon mutation plus common mutations (EGFRum+EGFRcm, n = 52), complex uncommon mutations (complex EGFRum, n = 22), and single uncommon mutations (single EGFRum, n = 28) were significantly different (ORRs: 76.3%, 61.5%, 54.5%, and 50.0%, respectively, p = 0.023; and mPFS: 13.3, 14.7, 8.1, and 6.0 months, respectively, p = 0.004). Afatinib showed superior efficacy over gefitinib/erlotinib/icotinib in EGFRcm (ORR: 81.0% vs. 75.0%, p = 0.773; mPFS: 19.1 vs. 12.0m, p = 0.036), EGFRum+EGFRcm (ORR: 100% vs. 54.5%, p = 0.017; mPFS: NE vs. 13.6m, p = 0.032), and single EGFRum (ORR: 78.6% vs. 21.4%, p = 0.007; mPFS: 10.1 vs. 3.0m, p = 0.025) groups. Comprehensive genomic profiling by Next Generation Sequencing encompassing multiple cancer-related genes was performed on 51/102 patients; the mPFS of patients without co-mutation (n = 16) and with co-mutations of tumor-suppressor genes (n = 31) and driver oncogenes (n = 4) were 31.1, 9.2, and 12.4 months, respectively (p = 0.046). TP53 mutation was the most common co-alteration and showed significantly shorter mPFS than TP53 wild-type patients (7.0 vs. 31.1m, p < 0.001). Multivariate analysis revealed that concurrent 19del/L858R and tumor-suppressor gene alterations independently predicted better and worse prognosis in patients with uncommon mutations, respectively.ConclusionsUncommon EGFR mutations constitute a highly heterogeneous subgroup of NSCLC that confer different sensitivities to EGFR-TKIs with regard to the mutation patterns. Afatinib may be a better choice for most uncommon EGFR mutations. Concurrent 19del/L858R and tumor-suppressor gene alterations, especially TP53, can be established as prognostic biomarkers.

scholarly journals FRMPD1 activates the Hippo pathway via interaction with WWC3 to suppress the proliferation and invasiveness of lung cancer cells

2019 ◽  
Vol Volume 11 ◽  
pp. 3395-3410 ◽  
Author(s):  
Xuezhu Rong ◽  
Qiang Han ◽  
Xuyong Lin ◽  
Joachim Kremerskothen ◽  
Enhua Wang
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Hippo Pathway ◽  
Lung Cancer Cells ◽  
The Hippo Pathway

scholarly journals α-Catenin levels determine direction of YAP/TAZ response to autophagy perturbation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mariana Pavel ◽  
So Jung Park ◽  
Rebecca A. Frake ◽  
Sung Min Son ◽  
Marco M. Manni ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Hippo Pathway ◽  
Cell Types ◽  
Autophagy Induction ◽  
Growth Promoting ◽  
Cellular Identity ◽  
The Hippo Pathway ◽  
Different Cell Types ◽  
Autophagy Inhibition

AbstractThe factors regulating cellular identity are critical for understanding the transition from health to disease and responses to therapies. Recent literature suggests that autophagy compromise may cause opposite effects in different contexts by either activating or inhibiting YAP/TAZ co-transcriptional regulators of the Hippo pathway via unrelated mechanisms. Here, we confirm that autophagy perturbation in different cell types can cause opposite responses in growth-promoting oncogenic YAP/TAZ transcriptional signalling. These apparently contradictory responses can be resolved by a feedback loop where autophagy negatively regulates the levels of α-catenins, LC3-interacting proteins that inhibit YAP/TAZ, which, in turn, positively regulate autophagy. High basal levels of α-catenins enable autophagy induction to positively regulate YAP/TAZ, while low α-catenins cause YAP/TAZ activation upon autophagy inhibition. These data reveal how feedback loops enable post-transcriptional determination of cell identity and how levels of a single intermediary protein can dictate the direction of response to external or internal perturbations.

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