osteoprotegerin and Carcinoma--Hepatocellular

Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; MicroRNAs; Osteoprotegerin; p38 Mitogen-Activated Protein Kinases; Protein Phosphatase 1; RNA, Long Noncoding

Bone is the second most frequent site of metastasis for HCC, which leads to an extremely poor prognosis. HCC bone metastasis is typically osteolytic, involving the activation of osteoclasts. Long noncoding RNA H19 plays an important role in the pathogenesis of human cancers. Nonetheless, the mechanism underlying the participation of H19 in HCC bone metastasis remains unclear.. The current study established a mouse HCC bone metastasis model by using serial intracardiac injection and cell isolation to obtain cells with distinct bone metastasis ability. H19 was highly expressed in these cells and in clinical HCC bone metastasis specimens. Both osteoclastogenesis in vitro and HCC bone metastasis in vivo were promoted by H19 overexpression, whereas these processes were suppressed by H19 knockdown. H19 overexpression attenuated p38 phosphorylation and further down-regulated the expression of osteoprotegerin (OPG), also known as osteoclastogenesis inhibitory factor. However, up-regulated OPG expression as well as suppressed osteoclastogenesis caused by H19 knockdown were recovered by p38 interference, indicating that p38 mitogen-activated protein kinase (MAPK)-OPG contributed to H19-promoted HCC bone metastasis. Furthermore, we demonstrated that H19 inhibited the expression of OPG by binding with protein phosphatase 1 catalytic subunit alpha (PPP1CA), which dephosphorylates p38. SB-203580-mediated inactivation of p38MAPK reversed the down-regulation of HCC bone metastasis caused by H19 knockdown in vivo. Additionally, H19 enhanced cell migration and invasion by up-regulating zinc finger E-box binding homeobox 1 through the sequestration of microRNA (miR) 200b-3p.. H19 plays a critical role in HCC bone metastasis by reducing OPG expression, which is mediated by the PPP1CA-induced inactivation of the p38MAPK pathway; and H19 also functions as a sponge for miR-200b-3p.

Topics: Animals; Bone Neoplasms; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Imidazoles; Liver Neoplasms; Male; Mice; MicroRNAs; Osteoprotegerin; p38 Mitogen-Activated Protein Kinases; Protein Phosphatase 1; Pyridines; RAW 264.7 Cells; RNA, Long Noncoding; Up-Regulation; Zinc Finger E-box-Binding Homeobox 1

IKK-NF-kappaB signaling is regarded as an important factor in hepatocarcinogenesis and a potential target for liver cancer therapy. Therefore, in this study, we analyzed the expression of mRNAs encoding components and targets of NF-kappaB signaling including IKKalpha, IKKbeta, RANK, RANKL, OPG, CyclinD3, mammary serine protease inhibitor (Maspin), CyclinD1, c-FLIP, Bcl-xl, Stat3, Cip1 and Cip2 by real-time PCR in 40 patients with liver cancer. After statistical analysis, 7 indices including IKKalpha, IKKbeta, RANK, Maspin, c-FLIP, Cip2 and cyclinD1 were found to show significant differences between tumor tissue and its corresponding adjacent tissue. When IKKalpha and IKKbeta were downregulated in the hepatocellular carcinoma (HCC) cell lines of MHCC-97L and MHCC-97H in vitro, the numbers of BrdU positive cells were decreased in both IKKalpha and IKKbeta knockdown cells. Levels of apoptosis were also investigated in IKKalpha and IKKbeta knockdown cells. The growth of HCC was inhibited in the subcutaneous implantation model, and lung metastatogenesis was also significantly inhibited in the kidney capsule transplantation model. Downregulation of IKKalpha and IKKbeta in HCC cultured in vitro revealed that increased Maspin, OPG and RANKL expression was associated with metastasis of HCC. These findings were associated with downregulation of Bcl-XL and c-FLIP, which may be the reason for increased apoptosis. The therapeutic effect of IKKalpha and IKKbeta downregulation depends on extent of NF-kappaB inhibition and the malignant nature of the HCC. We anticipate that IKK-targeted gene therapy can be used in the treatment of HCC, a cancer that is notoriously resistant to radiation and chemotherapy.

Topics: Animals; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Cyclin D1; Flow Cytometry; Gene Expression; Gene Expression Profiling; Humans; I-kappa B Kinase; Immunohistochemistry; Liver Neoplasms; Mice; Mice, Nude; NF-kappa B; Osteoprotegerin; RANK Ligand; Reverse Transcriptase Polymerase Chain Reaction; Serpins; Signal Transduction; Xenograft Model Antitumor Assays

Giant cell tumor (GCT) of bone is a primary osteolytic tumor that is characterized by the formation of osteoclast-like giant cells. In addition to GCT of bone, extraskeletal GCT are known to be formed in several soft tissues. Giant cells in GCT of bone were suggested to be identical to osteoclasts, but the characterization of giant cells in extraskeletal GCT remains incomplete. In this study, a case of sarcomatoid hepatocellular carcinoma with osteoclast-like giant cells was analyzed. Immunohistochemistry revealed the expression of almost all markers of osteoclasts: tartrate-resistant acid phosphatase, CD68, CD51, CD54 and matrix metalloprotease-9, in osteoclast-like giant cells in the tumor. In situ hybridization revealed the expression of receptor activator of nuclear factor-kappa B (RANK) in the giant cells and receptor activator of nuclear factor-kappa B ligand (RANKL) in the tumor cells. The hepatic origin of the sarcomatoid hepatocellular carcinoma cells was confirmed by the expression of albumin. This is the first report suggesting that hepatocyte-derived cells possess the potential for osteoclastogenesis. In addition, these findings suggest that osteoclast-like cells in the hepatocellular carcinoma were formed by the same mechanism as osteoclastogenesis in bone.

Topics: Aged; Albumins; Biomarkers; Carcinoma, Hepatocellular; Carcinosarcoma; Carrier Proteins; Cell Transformation, Neoplastic; Fatal Outcome; Giant Cells; Glycoproteins; Hepatocytes; Humans; Immunohistochemistry; In Situ Hybridization; Liver Neoplasms; Male; Membrane Glycoproteins; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger