Abstract
BackgroundDue to the difficulties in early diagnosing and treating hepatocellular carcinoma (HCC), prognoses for patients remained poor in the past decade. In this study, we established a screening model to discover novel prognostic biomarkers in HCC patients.MethodsCandidate biomarkers were screened by liquid chromatography with tandem mass spectrometry (LC-MS/MS) analyses of five HCC normal (N)/tumor (T) paired tissues and preliminarily verified them through several in silico database analyses. Expression levels and functional roles of candidate biomarkers were respectively evaluated by immunohistochemical staining in N/T paired tissue (n = 120) and MTS, colony formation, and transwell migration/invasion assays in HCC cell lines. Associations of clinicopathological features and prognoses with candidate biomarkers in HCC patients were analyzed from GEO and TCGA datasets and our recruited cohort.ResultsWe found that the transmembrane P24 trafficking protein 9 (TMED9) protein was elevated in HCC tissues according to a global proteomic analysis. Higher messenger (m)RNA and protein levels of TMED9 were observed in HCC tissues compared to normal liver tissues or pre-neoplastic lesions. The TMED9 mRNA expression level was significantly associated with an advanced stage and a poor prognosis of overall survival (OS, p = 0.00084) in HCC patients. Moreover, the TMED9 protein expression level was positively correlated with vascular invasion (p = 0.026), OS (p = 0.044), and disease-free survival (p = 0.015) in our recruited Taiwanese cohort. In vitro, manipulation of TMED9 expression in HCC cells significantly affected cell migratory, invasive, proliferative, and colony-forming abilities.ConclusionsOurs is the first work to identify an oncogenic role of TMED9 in HCC cells and may provide insights into the application of TMED9 as a novel predictor of clinical outcomes and a potential therapeutic target in patients with HCC.
Highlights
Due to the difficulties in early diagnosing and treating hepatocellular carcinoma (HCC), prognoses for patients remained poor in the past decade
Protein IDs were identified by a Mascot engine through searching the SWISS-PROT database, and protein expression levels were calculated according to Mascot scores
Β-catenin, GLI1, p-ERK, p-signal transducer and activator of transcription 3 (STAT3), and secreted transforming growth factor (TGF)-α were all upregulated in Transmembrane P24 trafficking protein 9 (TMED9)-overexpressed HCC36 cells (Fig. 6f). These results suggested that CNIH4/TGF-α/GLI1 and WNT/β-catenin pathways might be involved in TMED9-induced HCC progression and these issues should be further investigated in future research
Summary
Due to the difficulties in early diagnosing and treating hepatocellular carcinoma (HCC), prognoses for patients remained poor in the past decade. We established a screening model to discover novel prog‐ nostic biomarkers in HCC patients. Hepatocellular carcinoma (HCC) is the most fatal malignancy disease among primary liver cancers and is one of the leading causes of cancer-related deaths worldwide [1]. The incidence of HCC is highest in Asia, including Taiwan, and Africa, and it occurs in males more often than in females [5]. Several therapeutic strategies have been applied as HCC treatment, including chemoradiotherapy, surgery, and systemic therapy with sorafenib [7, 8], but low therapeutic and diagnostic efficiencies still lead to severe mortality of patients with this disease. We wanted to illuminate novel biomarkers for HCC diagnoses or therapeutic targets
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