Molecular targeting striatins (STRNs) in connection with the Stripak complex in human solid cancers

Li, Xinyu 2025. Molecular targeting striatins (STRNs) in connection with the Stripak complex in human solid cancers. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Background. The Striatin-Interacting Phosphatase And Kinase (STRIPAK) protein complex has emerged as a key regulator of multiple signalling pathways, with its dysregulation implicated in various pathological conditions, particularly in cancer deployment and progression. Previous research has highlighted the pivotal role of its scaffolding proteins, Striatins (STRNs), in orchestrating the complex formation and subcellular targeting. Targeting this central component may therefore offer novel insights into disease mechanisms and support the development of targeted therapeutic interventions. Although the clinical relevance of some individual STRIPAK components has begun to be recognised, no studies have comprehensively evaluated the collective significance of the entire STRIPAK complex in cancer. The current study investigated the clinical significance of both individual STRIPAK components and the integrated expression profile of the complex in pancreatic cancer and explored the molecular mechanism by which the key STRIPAK scaffold protein STRN3 contributed to the biological aspect of cancer cells. Methods. Cohort of pancreatic cancer was used to test the expression profile of STRNs and the STRIPAK members and their relationship with the outcome of the patients. Cancer cell models with differential expression of STRN3 were created and evaluated the biological impact of loss of STRN3 on cancer cells. Protein kinase array platforms were employed to search for potential signalling partners of STRN3, supported by a comprehensive number of cellular and biochemical techniques. Results. It was found that the STRIPAK complex possesses highly significant and independent value in predicting the outcome of the patients, including overall survival and disease-free survival in pancreatic cancer. A series of submodules from human pancreatic cancer cell lines models were also created to allow different levels of STRN3 expression. With the cell models, the study established a strong link between STRN1 and STRN3 expression and key cellular processes such as adhesion, migration, proliferation, and, interestingly, cellular response to chemotherapy. Proteomic based screening identified that the leading protein responders to STRN manipulation were key autophagy markers, namely SQSTM1 and BECN1, which responded as prominent regulatory partners of STRN3, arguing the pivotal role of autophagy in STRNs-mediated cancer progression. The study went on to confirm that STRN3 contributes to both ends of the autophagy process. Specifically, STRN3 contributes to the activation of the AMPK-ULK1-BECN1 signalling cascade, thereby promoting autophagy initiation. In addition, STRN3 physically interacts with SQSTM1 and LC3, which serve as surrogate markers for autophagic flux, and plays a significant role in autophagic degradation. Conclusion. The study provides valuable insights into the potential signalling mechanisms through which STRNs regulate cancer development and progression. This project contributes to the identification of novel genetic biomarkers with significant implications for clinical applications and targeted therapeutic strategies. Clinically, the development of multi- biomarker panels incorporating STRIPAK components may further enhance diagnostic accuracy and reduce the risk of false-positive and false-negative results compared to reliance on single markers.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	4 April 2025
Last Modified:	04 Apr 2025 15:11
URI:	https://orca.cardiff.ac.uk/id/eprint/177415

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