Mechanisms of the metastatic action of EPLIN (LIMA1) and molecular targeting in solid cancers

Wang, Cai 2025. Mechanisms of the metastatic action of EPLIN (LIMA1) and molecular targeting in solid cancers. MD Thesis, Cardiff University. Item availability restricted.

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Abstract

Head and neck cancer (HNC) represents a major clinical challenge due to its aggressive nature, poor prognosis, and frequent resistance to existing therapies. While EPLIN has been widely recognised as a tumour suppressor and may influence drug sensitivity in multiple cancer types such as colorectal, gastric and breast cancers, it has been recently shown that this role may be cancer type dependent as recent report revealed that EPLIN may play a potential oncogenic role in other cancer types such as pancreatic cancer. However, its role in HNC has remained largely unexplored. My MD study aimed to investigate the functional, molecular, and clinical implications of EPLIN in HNC, and to clarify whether it contributes to tumour progression in a cancer type–specific manner. Through transcriptomic analyses, I identified a distinct expression profile of EPLIN in HNC in that highly expressed EPLIN is associated with a disease progression and a poor clinical outcome of the patients, a pattern in sharp contrast with its known suppressive role in colorectal cancer. A set of HNC cancer cell models were constructed with differential expression level of EPLIN, namely EPLIN knockdown expression or EPLIN over-expression. Using these cell models, the functional assays revealed that EPLIN promotes key cancer-related behaviours, including proliferation, adhesion, migration, and invasion in HNC cells. Further investigations using clinical cohorts revealed that EPLIN exhibited significant and specific positive correlations with some of the key cytoskeletal and focal adhesion proteins including paxillin (PXN), integrin-alpha3 and actinin-1 (ACTN1) in HNC, correlations not seen in colorectal cancer. Furthermore, experimental work by proteomic analysis, coimmunoprecipitation, immunofluorescence, and subcellular localisation studies have confirmed the interaction between the EPLIN protein, paxillin and actinin-1 proteins, indicating that these proteins form an EPLIN–paxillin–actinin-1 signature in HNC. Additional validation study with clinical cohort validated that this three-protein signature does indeed provide a more powerful predictive tool for the disease progression, a finding not seen in cancer types in which EPLIN acting as a tumour suppressor, namely colorectal cancer, renal clear cell carcinoma and gastric cancer. Thus, these interactions point to the important role of EPLIN interactive proteins in a pro-metastatic molecular network in aggressive HNC. Finally, the study explored the therapeutic value of EPLIN in head and neck cancers and found that EPLIN only has limited value in influencing sensitivity of cell to chemotherapeutic drugs, an area requiring additional exploration. Separately, through transcriptomic and proteomics analyses, the study has identified a surprising EPLIN protein interactive partner, namely FAM171A2. The interactive relationship between the EPLIN protein and FAM171A2 protein was further supported by experimental validation, which confirmed a direct interaction between EPLIN and FAM171A2 in HNC cell models. FAM171A2 is a protein with little knowledge of its function and the precise mechanism through which EPLIN regulates or cooperates with FAM171A2 remains unclear. Notably, this EPLIN–FAM171A2 interaction was significant in HNC and pancreatic cancer, but absent in colorectal and kidney cancers, suggesting that their functional interaction may be specific to these two cancer types in which EPLIN exerts as a potential triggering mechanism for EPLIN’s oncogenic properties. Further mechanistic studies will be required to clarify the biological significance and downstream consequences of this interaction. Finally, the study explored the prospect of therapeutically targeting EPLIN in head and neck cancer. Using virtual drug screen programme and drug docking programme, we screened a wide range of existing drugs with known chemical structure and have surprisingly identified an existing drug, digoxin which is able to dock onto the EPLIN protein. Using head and neck cell models created which had different EPLIN expression level, I have tested the impact of digoxin on these cancer cells and have confirmed that digoxin modulates cytoskeletal dynamics and inhibited cellular behaviour that are linked with metastatic property of cancer cells including inhibition of cellular migration, in vitro invasion and matrix adhesion. The inhibition by digoxin was seen in an EPLIN-dependent manner. In summary, my study demonstrated that EPLIN may act as an oncogene in HNC by promoting cytoskeletal reorganisation and interacting with key focal adhesion proteins. These findings highlight EPLIN as a potential biomarker and therapeutic target in HNC and provide a framework for further mechanistic and therapeutic exploration.

Item Type:	Thesis (MD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	11 September 2025
Last Modified:	11 Sep 2025 13:44
URI:	https://orca.cardiff.ac.uk/id/eprint/181042

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