Abstract
Increasing significance of tumor–stromal interaction in development and progression of cancer implies that signaling molecules in the tumor microenvironment (TME) might be the effective therapeutic targets for hepatocellular carcinoma (HCC). Here, the role of microRNA miR-199a-3p in the regulation of TME and development of HCC has been investigated by several in vitro and in vivo assays. Expression of miR-199a-3p was observed significantly low in HCC tissues and its overexpression remarkably inhibited in vivo tumor growth and metastasis to lung in NOD-SCID mice. In vitro restoration of miR-199a-3p expression either in endothelial cells (ECs) or in cancer cells (CACs) significantly diminished migration of ECs in co-culture assay. Again incubation of miR-199a-3p transfected ECs with either conditioned media (CM) of CACs or recombinant VEGF has reduced tube formation, in ECs and it was also dropped upon growth in CM of either anti-VEGF antibody-treated or miR-199a-3p-transfected CACs. In addition, bioinformatics and luciferase-reporter assays revealed that miR-199a-3p inhibited VEGF secretion from CACs and VEGFR1 and VEGFR2 expression on ECs and thus restricted cross talk between CACs and ECs. Again, restoration of miR-199a-3p in hepatic stellate cells (HSCs) reduced migration and invasion of CACs in co-culture assay, while it was enhanced by the overexpression of HGF suggesting miR-199a-3p has hindered HSC-CACs cross talk probably by inhibiting HGF and regulating matrix metalloproteinase MMP2, which were found as targets of miR-199a-3p subsequently by luciferase-reporter assay and gelatin zymography, respectively. Thus, these findings collectively highlight that miR-199a-3p restricts metastasis, invasion and angiogenesis in HCC and hence it may be considered as one of the powerful effective therapeutics for management of HCC patients.
Highlights
Reciprocal signaling between tumor cells and the stromal components of surrounding tumor microenvironment (TME) is the fundamental to the evolution and metastasis of solid tumors including hepatocellular carcinoma.[1,2,3,4] This complex dynamic network orchestrated mainly by cancer cells (CACs) and coherently activated stromal cells (SCs) such as fibroblasts or cancer-associated fibroblasts (CAFs), hepatic stellate cells (HSCs), endothelial cells (ECs; tumor-associated ECs), nonhepatic tumor infiltrating immune cells.[5]
During HCC progression in response to paracrine signal from injured hepatocytes, normal fibroblasts or HSCs differentiate into myofibroblast-like cells,[8,9] which secrete many mitogenic and motogenic factors such as hepatocyte growth factor (HGF), fibroblast growth factor (FGF), platelet derived growth factor (PDGF), transforming growth factor β1 (TGFβ1), matrix metalloproteinases (MMPs) and extracellular matrix (ECM) to create a complex milieu in TME, whereas CACs exude TGFβ1, PDGF, VEGF that activate other SCs.[10,11,12,13]
Recent reports suggest that inflammation and activation of HSCs in a bidirectional cross talk between CACs and HSCs orchestrate a favorable microenvironment for the growth of HCC6,7 and TGFβ mediates cross talk between malignant hepatocyte and tumor-associated macrophages (TAM) through ECM remodeling and angiogenesis.[30]
Summary
Reciprocal signaling between tumor cells and the stromal components of surrounding tumor microenvironment (TME) is the fundamental to the evolution and metastasis of solid tumors including hepatocellular carcinoma.[1,2,3,4] This complex dynamic network orchestrated mainly by cancer cells (CACs) and coherently activated stromal cells (SCs) such as fibroblasts or cancer-associated fibroblasts (CAFs), hepatic stellate cells (HSCs), endothelial cells (ECs; tumor-associated ECs), nonhepatic tumor infiltrating immune cells.[5]. The functional implication of this complex cross communications among CACs, HSCs, ECs and ECM remodeling, which is Received 15.7.16; revised 30.1.17; accepted 22.2.17; Edited by G Calin miR-199a-3p inhibits tumor–stroma cross talk in HCC A Ghosh et al an important area of potential systematic drug development for the management of HCC, has not been explored explicitly. 3p is anticipated with the overexpression of HGF receptor cMET,[25] the cell surface adhesion molecule CD4426 and mTOR of AKT/mTOR signaling pathway.[27] In addition, we have observed in this study that restoration of miR-199a-3p restricted tumor growth and extrahepatic metastasis in mice and angiogenesis, migration and invasion of cancer cells by downregulating five new components from TME of HCC and abrogated cross talk between HSCs–CACs and CACs–ECs implicating high therapeutic potential of this miRNA for the management of HCC
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