Abstract
PurposeHepatocellular carcinoma (HCC) accounts for more than 80% of primary liver cancers and is one of the leading causes of cancer-related death in many countries. Cancer cell-derived exosomes are shown to mediate communications between cancer cells and the microenvironment, promoting tumorigenesis. Hedgehog signaling pathway plays important roles in cancer development of HCC.MethodsExosomes were isolated from culture medium of HCC cell lines PLC/PRF/5 and MHCC-97H and were found to promote cancer cell growth measured with cell proliferation and colony formation assay. HCC cells cultured with cancer cell-derived exosome had increased cancer stem cell (CSC) population demonstrated by increased cell sphere formation CSC marker expressions. Hedgehog protein Shh was found to be highly expressed in these two HCC cell lines and preferably carried by exosomes. When Shh was knocked down with shRNA, the resulting exosomes had a reduced effect on promoting cancer cell growth or CSC population increase compared to normal cell-derived exosomes.ResultsThe ability of PLC/PRF/5 cells to form tumor in a xenograft model was increased by the addition of the exosomes from control cancer cells but not the exosomes from Shh knocked down cancer cells. Finally, the higher plasma Exo-Shh levels were associated with later tumor stages, higher histological grades, multiple tumors, and higher recurrence rates.ConclusionThis study demonstrated that HCC cells secreted Shh via exosome and promote tumorigenesis through the activated Hedgehog pathway.
Highlights
Hepatocellular carcinoma (HCC), accounting for nearly 80% of the total number of liver cancers, is the fourth most common cause of death related to cancer [1]
To understand whether Extracellular vesicles (EVs) would play a role in HCC development, we extracted and separated EVs secreted by HCC cell lines PLC/PRF/5 and MHCC-97H, as well as the normal human liver cell line L02 using ultracentrifugation
We found that in both PLC/PRF/5 and MHCC-97H cells, the messenger RNAs (mRNAs) and protein levels of several target genes, including GLI1, PTCH1, Cmyc, and CyclinD1, were all elevated when Exo was added in the culture medium (Figures 3E, F)
Summary
Hepatocellular carcinoma (HCC), accounting for nearly 80% of the total number of liver cancers, is the fourth most common cause of death related to cancer [1]. The nonoperative treatments include transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA), and systematic administration of Hedgehog Pathway in HCC targeted therapy represented by sorafenib. Better understanding the biology of HCC and developing more therapeutic targets are still needed for improving the outcome. The Hedgehog signaling pathway is a master regulator in animal development. First discovered in Drosophila, Hedgehog is a conserved morphogen secreted to regulate differentiation process in many metazoans. The canonical Hedgehog pathway involves the binding of Hedgehog protein to a 12transmembrane receptor PTCH1, releasing the G-proteincoupled receptor smoothened (SMO) from its inhibitory effect. Activated SMO in turn releases transcription factor GLI1 (glioma-associated oncogene family members) from its inhibitors SUFU and KIF7. The released GLI1 is translocated into nucleus and activates transcription of a number of genes, including GLI1, PTCH1, Cyclin D, Cmyc, and VEGF. Three homologs of Hedgehog proteins, sonic (Shh), Indian (Ihh), and desert (Dhh) have been identified, of which Shh is the most broadly expressed and asserts its function through paracrine or autocrine fashion
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