Functional and clinical significance of EPLIN in the progression of gastrointestinal cancers

Zeng, Jianyuan 2022. Functional and clinical significance of EPLIN in the progression of gastrointestinal cancers. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Colorectal cancer and pancreatic cancer rank as the 4th and 10th most common cancer types in the UK, and both are a deadly threat to people, thus also they have become a heavy social burden. Poor survival rates at the more aggressive stages and frequently reported drugs resistance encouraged researchers to try to gain more understanding of the development of such cancers and hunt for novel bio markers to developing treatments to improve outcomes. My PhD study focussed on establishing the functional and clinical implication of EPLIN on colorectal cancer and pancreatic cancer, as well as its impact on drug resistance. Potential interacting partners and signalling events were also investigated to understand possible the mechanistic network of EPLIN in colorectal cancer. EPLIN expression was downregulated in human clinical colorectal cancer tissues at transcript and protein level and its downregulation worsened clinical outcomes of colorectal cancer patients. By manipulating expression of EPLIN in colorectal cancer cell lines, EPLIN regulates cellular growth, adhesion, migration and invasion negatively. Protein microarray revealed potential interacting partners and related signalling events of EPLIN. Further I followed up with two of the priority partners, HSP60 and Her2, and performed co-IP assays as well as manipulated EPLIN/HSP60 expressions in colorectal cancer cells to reveal that EPLIN and HSP60 had a negative correlation with Her2 but not a close protein-protein interaction. High level of HSP60 was observed in colorectal cancer at transcript and protein level. Clinical implication of such molecules was also investigated by revisiting a colorectal cancer cohort, the higher level of Her2 led to worse overall survival (OS) and disease-free survival (RFS), while the combination of aberrant expression of EPLIN/Her2/HSP60 resulted in worst clinical outcomes within control groups and was identified as one of the factors to affect the OS and RFS as well. Moreover, inhibition of EPLIN and HSP60 in colorectal cancer cell lines led to dysregulation of cells’ response to chemotherapeutic and EGFR/Her2 targeted therapeutic agents. Such dysregulation might be related to the correlated relationship between these molecules or mitochondrial metabolism. In my study, I also demonstrated that EPLIN was related to carcinogenesis in pancreatic cancer. Its expression was upregulated in tumour samples at transcript and protein level and related to aggressiveness. The presence of EPLIN led to worse clinical outcomes of pancreatic cancer patients. In conclusion, my study explored and demonstrated EPLIN’s implication on clinical outcomes, cellular functions and drugs resistances as well as shed light on mechanisms of action of EPLIN in colorectal cancer. This study also challenges the tumour suppressor role that EPLIN plays, and suggests it promotes the development of pancreatic cancer.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	20 October 2022
Last Modified:	18 Oct 2023 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/153494

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