Abstract
Exosomes play an important role in intercellular communication and metastatic progression of hepatocellular carcinoma (HCC). However, cellular communication between heterogeneous HCC cells with different metastatic potentials and the resultant cancer progression are not fully understood in HCC. Here, HCC cells with high-metastatic capacity (97hm and Huhm) were constructed by continually exerting selective pressure on primary HCC cells (MHCC-97H and Huh7). Through performing exosomal miRNA sequencing in HCC cells with different metastatic potentials (MHCC-97H and 97hm), many significantly different miRNA candidates were found. Among these miRNAs, miR-92a-3p was the most abundant miRNA in the exosomes of highly metastatic HCC cells. Exosomal miR92a-3p was also found enriched in the plasma of HCC patient-derived xenograft mice (PDX) model with high-metastatic potential. Exosomal miR-92a-3p promotes epithelial-mesenchymal transition (EMT) in recipient cancer cells via targeting PTEN and regulating its downstream Akt/Snail signaling. Furthermore, through mRNA sequencing in HCC cells with different metastatic potentials and predicting potential transcription factors of miR92a-3p, upregulated transcript factors E2F1 and c-Myc were found in high-metastatic HCC cells promote the expression of cellular and exosomal miR-92a-3p in HCC by directly binding the promoter of its host gene, miR17HG. Clinical data showed that a high plasma exosomal miR92a-3p level was correlated with shortened overall survival and disease-free survival, indicating poor prognosis in HCC patients. In conclusion, hepatoma-derived exosomal miR92a-3p plays a critical role in the EMT progression and promoting metastasis by inhibiting PTEN and activating Akt/Snail signaling. Exosomal miR92a-3p is a potential predictive biomarker for HCC metastasis, and this may provoke the development of novel therapeutic and preventing strategies against metastasis of HCC.
Highlights
Hepatocellular carcinoma (HCC) is a deadly form of cancer and is the most common liver cancer worldwide [1]. some progress have recently been made in clinical diagnosis and treatment, late diagnosis and metastasis of HCC remain the main causes of high mortality, extremely threatening the long-term prognosis of HCC patients [2, 3]
Some progress have recently been made in clinical diagnosis and treatment, late diagnosis and metastasis of HCC remain the main causes of high mortality, extremely threatening the long-term prognosis of HCC patients [2, 3]
To verify our hypothesis that migration ability might be transferred among cancer cells through the bioactive substance in cell supernatant, conditioned media (CM) from Huh7, SK-Hep1, and Hep-3B were utilized to study their effect on Huh7 cells
Summary
Hepatocellular carcinoma (HCC) is a deadly form of cancer and is the most common liver cancer worldwide [1]. some progress have recently been made in clinical diagnosis and treatment, late diagnosis and metastasis of HCC remain the main causes of high mortality, extremely threatening the long-term prognosis of HCC patients [2, 3]. Hepatocellular carcinoma (HCC) is a deadly form of cancer and is the most common liver cancer worldwide [1]. Factors that promote malignancy and subsequent metastasis in HCC have not been fully elucidated. A comprehensive understanding of HCC metastasis and its underlying molecular mechanism can promote the development of potential therapeutic interventions against metastatic HCC. Cancer cells in a tumor can be viewed as a heterogeneous population of individual cells, including cancer-initiating cells and highly or less differentiated cancer cells with morphological and functional differences [7, 8]. Intratumor heterogeneity can arise from the somatic accumulation of mutations and cellular differentiation. Many studies have revealed that intratumor heterogeneity could be induced by exerting selective pressures in the tumor. Intercommunication within cells or other factors in the microenvironment can foster the evolution of cancer cells
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