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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
Published on: September 13, 2018
Expression of Hippo Pathway Molecules in Distal Bile Duct Cancer
Ki Rim Lee1, Soon Auck Hong, Mineui Hong
1Department of Pathology, College of Medicine, Chung-Ang University, Chung-Ang University Hospital, Seoul, South Korea.
Abstract:
The Hippo pathway is a tumor-suppressive pathway. Hippo pathway dysregulation correlates with cancer progression, metastasis, and a poor prognosis. Large tumor suppressor homolog 1/2 (LATS1/2), Yes-associated protein (YAP), and TEA domain-containing sequence-specific transcription factor 4 (TEAD4) are primary Hippo pathway components. We evaluated LATS1/2, YAP, and TEAD4 expression and their correlation with clinicopathological behavior and prognostic significance in 67 distal bile duct cancer (DBDC) cases. LATS1/2 expression was observed in 20 (29.9%) DBDC cases and correlated significantly with low pT classification, absence of lymphovascular invasion, and low American Joint Committee on Cancer (AJCC) stage. High YAP expression was identified in 35 (52.2%) cases and correlated with high pT classification, AJCC stage, and TEAD4 expression. High TEAD4 expression was observed in 13 (19.4%) cases and correlated significantly with lymph node metastasis, involved resection margins, and high AJCC stage. Overall survival was significantly better in patients with DBDC with than in those without LATS1/2 expression ( P < 0.001), and significantly worse in patients with high than in those with low YAP and TEAD4 expression ( P = 0.014, 0.037, respectively). The overall survival of patients with combined LATS1/2 + YAP or TEAD4 low expression was significantly better than that of other groups [hazard ratio (HR) 5.809; 95% CI, 1.770-19.065; P = 0.001]. This combination was an independent good prognostic factor (HR 4.399; 95% CI, 1.313-14.743; P = 0.016) in patients with DBDC. LATS1/2, YAP, and TEAD4 expression correlates with DBDC clinicopathological behavior and may be useful prognostic markers in patients with DBDC.
Insights
Hippo pathway components Large tumor suppressor homolog 1/2 (LATS1/2), Yes-associated protein (YAP), and TEA domain-containing sequence-specific transcription factor 4 (TEAD4) show prognostic significance in distal bile duct cancer. Their combined expression may serve as an independent prognostic factor for improved survival.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The Hippo pathway is a critical tumor suppressor pathway.
- Dysregulation of the Hippo pathway is implicated in cancer progression, metastasis, and poor prognosis.
- Key components include Large tumor suppressor homolog 1/2 (LATS1/2), Yes-associated protein (YAP), and TEA domain-containing sequence-specific transcription factor 4 (TEAD4).
Purpose of the Study:
- To evaluate the expression of LATS1/2, YAP, and TEAD4 in distal bile duct cancer (DBDC).
- To assess the correlation of these proteins with clinicopathological features and prognosis in DBDC patients.
- To determine the prognostic significance of individual and combined expression of LATS1/2, YAP, and TEAD4 in DBDC.
Main Methods:
- Immunohistochemical analysis of LATS1/2, YAP, and TEAD4 expression in 67 DBDC tissue samples.
- Correlation analysis with clinicopathological parameters such as pT classification, lymphovascular invasion, American Joint Committee on Cancer (AJCC) stage, lymph node metastasis, and resection margins.
- Overall survival analysis using Kaplan-Meier curves and Cox proportional hazards models.
Main Results:
- LATS1/2 expression (29.9%) correlated with favorable features (low pT, no lymphovascular invasion, low AJCC stage) and better overall survival (P < 0.001).
- High YAP (52.2%) and TEAD4 (19.4%) expression correlated with adverse features (high pT, high AJCC stage, lymph node metastasis, involved resection margins) and worse overall survival (P = 0.014, P = 0.037, respectively).
- Combined low expression of LATS1/2 with low YAP or TEAD4 was associated with significantly better overall survival and identified as an independent good prognostic factor (HR 4.399, P = 0.016).
Conclusions:
- LATS1/2, YAP, and TEAD4 expression levels are significantly associated with the clinicopathological behavior of distal bile duct cancer.
- These proteins serve as valuable prognostic markers for predicting patient outcomes in DBDC.
- The combined assessment of LATS1/2, YAP, and TEAD4 expression offers a promising strategy for improved prognostic evaluation in DBDC.
