Unbalanced YAP-SOX9 circuit drives stemness and malignant progression in esophageal squamous cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Yes-associated protein (YAP) is a key regulator of tissue homeostasis.
• The specific role and regulatory mechanisms of YAP in esophageal squamous cell carcinoma (ESCC) are not fully understood.

Purpose of the Study:

• To investigate the role of YAP in ESCC.
• To elucidate the regulatory mechanisms of YAP in ESCC.
• To explore YAP-SOX9 feedback loop as a potential therapeutic target in ESCC.

Main Methods:

• In vitro studies involving genetic or pharmacological inhibition of YAP.
• ESCC xenograft models to assess tumor growth and CSC marker expression.
• Analysis of YAP and SOX9 expression correlation in clinical cohorts.
• Investigation of microRNA-mediated regulation of YAP.
• Analysis of TCGA dataset for YAP gene amplification and Hippo pathway mutations.

Main Results:

• YAP inhibition repressed CSC-like properties (tumorsphere formation, motility, chemoresistance) in vitro.
• YAP inhibition attenuated tumor growth and CSC marker expression in ESCC xenografts.
• YAP transcriptionally activated SOX9 via TEAD1; YAP signaling correlated positively with SOX9 expression in clinical cohorts.
• SOX9-induced microRNAs, like miR-506-3p, negatively regulated YAP, forming a feedback loop.
• Dual inhibition of YAP and SOX9 robustly suppressed malignant phenotypes.
• YAP gene amplification and Hippo pathway regulator inactivation occurred in 44% of TCGA ESCC samples.
• Elevated nuclear YAP expression was observed in Chinese ESCC patient tissues.

Conclusions:

• Genetic hyperactivation of YAP unbalances the YAP-SOX9 feedback loop in ESCC.
• This imbalance confers cancer stem cell (CSC)-like features in ESCC.
• The YAP-SOX9 circuit represents a promising therapeutic target for ESCC treatment.