No abstract

Epithelial Protein Lost In Neoplasm (EPLIN), also known as LIMA1 (LIM Domain And Actin Binding 1), was first discovered as a protein differentially expressed in normal and cancerous cell lines. It is now known to be key to the progression and metastasis of certain solid tumours. Despite a slow pace in understanding the biological role in cells and body systems, as well as its clinical implications in the early years since its discovery, recent years have witnessed a rapid progress in understanding the mechanisms of this protein in cells, diseases and indeed the body. EPLIN has drawn more attention over the past few years with its roles expanding from cell migration and cytoskeletal dynamics, to cell cycle, gene regulation, angiogenesis/lymphangiogenesis and lipid metabolism. This concise review summarises and discusses the recent progress in understanding EPLIN in biological processes and its implications in cancer.

Death associated protein-3 (DAP3) was identified as a responsive protein to interferon-gamma-induced cell death which possibly exerts this regulation by interacting with DAP3 binding cell Death enhancer-1 (DELE1), a newly discovered mitochondrial stress protein in response to cell stress signals. Whilst DAP3 has been shown to be aberrantly expressed in several cancer types (i.e. breast cancer), little is known about the relationship between DAP3 and DELE1 in cancers. The present study examined the expression levels of both DAP3 and DELE1 in clinical colorectal cancers (CRCs), as well as their implication on chemoresistance and mechanism behind the action. Firstly, transcript levels of both DAP3 and DELE1 were quantitatively assessed in a clinical cohort of CRC (n=94). Tumour tissues had significantly higher levels of DAP3, but not DELE1 compared with normal tissues. Levels of DAP3 and DELE1 had a significant association with patient's clinical outcomes and local recurrence. DAP3 and DELE1 significantly correlated in normal colorectal tissues but not in tumour tissues. Secondly, the protein levels of DAP3 and DELE1 were evaluated in both normal and tumour colon tissues which showed that both proteins were highly aberrant in CRC tissues. In addition, both DAP3 and DELE1 at transcript and protein levels were identified as prognostic factors for patient's clinical outcomes. Furthermore, in in vitro assays, knocking down DAP3 or DELE1, and in particular both DAP3 and DELE1 together rendered the CRC cells more sensitive to chemotherapy drugs, consistent with clinical findings of the TCGA-COAD datasets. The acquisition of drug sensitivity following the genetic knockdown was independent of the mitochondrial metabolism, as neither DAP3 knockdown nor DELE1 knockdown showed a significant change. In summary, DAP3 and DELE1 are highly aberrant in CRCs, and both molecules are prognostic factors for patient's clinical outcomes and local recurrence, and are indicators for chemoresistance.

Epithelial protein lost in neoplasm (EPLIN) has been implicated as a suppressor of cancer progression. The current study explored EPLIN expression in clinical gastric cancer and its association with chemotherapy resistance. EPLIN transcript expression, in conjunction with patient clinicopathological information and responsiveness to neoadjuvant chemotherapy (NAC), was explored in two gastric cancer cohorts collected from the Beijing Cancer Hospital. Kaplan-Meier survival analysis was undertaken to explore EPLIN association with patient survival. Reduced EPLIN expression was associated with significant or near significant reductions of overall, disease-free, first progression or post-progression survival in the larger host cohort and Kaplan Meier plotter datasets. In the larger cohort EPLIN expression was significantly higher in the combined T1 + T2 gastric cancer group compared to the T3 + T4 group and identified to be an independent prognostic factor of disease-free survival and overall survival by multivariate analysis. In the smaller, NAC cohort, EPLIN expression was found to be significantly lower in tumour tissues than in paratumour tissues. EPLIN expression was significantly associated with responsiveness to chemotherapy which contributes to overall survival. Together, EPLIN appears to be a prognostic factor and may be associated with patient sensitivity to NAC.

Colorectal cancer is a serious threat to human health. Poor prognosis and frequently reported drug resistance urges research into novel biomarkers and mechanisms to aid in the understanding of the development and progression of colorectal cancer and to optimise therapeutic strategies. In the current study, we investigated the roles of a putative tumour suppressor, EPLIN, in colorectal cancer. Our clinical colorectal cancer cohort and online databases revealed a downregulation of EPLIN in colorectal cancer tissues compared with normal tissues. The reduced expression of EPLIN was associated with poor clinical outcomes of patients. In vitro cellular function assays showed that EPLIN elicited an inhibitory effect on cellular growth, adhesion, migration and invasion. Utilising a protein microarray on protein samples from normal and tumour patient tissues suggested HSP60, Her2 and other signalling events were novel potential interacting partners of EPLIN. It was further revealed that EPLIN and HSP60 were negative regulators of Her2 in colorectal cancer cells. The clinical cohort also demonstrated that expression of HSP60 and Her2 affected clinical outcomes, but most interestingly the combination of EPLIN, HSP60 and Her2 was able to identify patients with the most unfavourable clinical outcome by independently predicting patient overall survival and disease free survival. Furthermore, EPLIN and HSP60 exhibited potential to regulate cellular response to chemotherapeutic and EGFR/Her2 targeted therapeutic agents. In conclusion, EPLIN is an important prognostic factor for patients with colon cancer and reduced EPLIN in CRC contributes to aggressive traits of CRC cells and their responses to chemotherapeutic drugs. Collectively, EPLIN is a pivotal factor for the development and progression of colorectal cancer and has important clinical and therapeutic values in this cancer type.