Hepatocellular Carcinoma Migration Research Articles

RIG-I suppresses the migration and invasion of hepatocellular carcinoma cells by regulating MMP9.

The retinoic acid-induced protein I (Rig-I/Ddx58), (RIG-I) initiates a signaling cascade that induces innate immune defences which is associated with the production of typeI interferons (IFNs) and inflammatory cytokines to establish an antiviral state. Aberrant RIG-I signaling leads to inflammation, autoimmune diseases and cancer. However, the role of RIG-I in hepatocellular carcinoma (HCC) is still unknown. Here, we observed that RIG-I expression was downregulated in HCC tissues and loss of RIG-I expression was correlated with poor clinicopathological features. Additionally, we demonstrated that patients with positive RIG-I expression had a better 3-year survival and RIG-I was an independent factor for predicting the prognosis of HCC patients. Elevated RIG-I expression inhibited the proliferation, migration, and invasion of HCC. Inhibiting RIG-I with its specific siRNA was able to attenuate the malignant behavior of HCC cells. Moreover, RIG-I inhibited the invasive behavior through downregulating matrix metalloproteinase-9 (MMP9). Mechanistically, RIG-I enhances IFN-α response by amplifying IFN-α effecter signaling via strengthening STAT1 activation. Addressing this pathway, we identified that RIG-I may serve as a prognostic marker and that MMP9 may be a potential target of RIG-I in HCC.

MiR-1236 down-regulates alpha-fetoprotein, thus causing PTEN accumulation, which inhibits the PI3K/Akt pathway and malignant phenotype in hepatoma cells.

Alpha fetoprotein (AFP) is a clinical biomarker of hepatocellular carcinoma (HCC). Here, we found that miR-1236 is down-regulated, whereas AFP is highly expressed in HCC tissues and cells. We demonstrated that miR-1236 directly targets the 3'UTR of AFP and down-regulates its expression. Also, miR-1236 inhibited and AFP stimulated proliferation, migration, invasion and vasculogenic mimicry (VM) of HCC. In agreement, AFP over-expression counteracted the inhibitory effect of miR-1236. We demonstrated that AFP promoted the ubiquitination of PTEN, thus decreasing PTEN levels, while miR-1236 inhibited the PI3K/Akt pathway.

STAT3 regulates the migration and invasion of a stem‑like subpopulation through microRNA‑21 and multiple targets in hepatocellular carcinoma.

Despite advances in the detection and treatment of hepatocellular carcinoma (HCC), the prognosis remains poor partly due to recurrence or extra/intrahepatic metastasis. Stem‑like cancer cells are considered the source of malignant phenotypes including metastasis in various types of cancer. HCC side population (SP), considered as stem‑like cancer cells, plays an important role in the migration and invasion in HCC, while the mechanisms involved remain unknown. In the present study, high levels of STAT3 and phospho‑STAT3 were observed in MHCC97H SP cells compared with the main population (MP) cells. Inhibition of phospho‑STAT3 led to a reduction of miR‑21 expression, an increase of PTEN, RECK, and programmed cell death 4 (PDCD4) expression as well as the migration and invasion of SP cells. A set of rescue experiments was performed using different combinations of STAT3 inhibitor, miR‑21 mimics and siRNAs to observe the expression of miR‑21 targets, cell migration and invasion alterations. Data indicated that the alterations induced by STAT3 inhibition were partly reversed by the upregulation of miR‑21. Additionally, the cells migration and invasion when silencing the targets of miR‑21 were also reversed by STAT3 inhibition. In conclusion, the present study revealed the aberrant expression of STAT3 and miR‑21 in HCC SP cells. Targeting STAT3 may limit HCC migration and invasion, which is likely to involve the regulation of miR‑21 and its targets PTEN, RECK and PDCD4. Strategies directed towards STAT3 may therefore be a novel approach for the treatment of HCC.

Antrodia cinnamomea Inhibits Migration in Human Hepatocellular Carcinoma Cells: The Role of ERp57 and PGK-1.

Evidences suggest that ERp57 and PGK-1 signaling lead to cancer cell proliferation and migration. We hypothesized that ERp57 and PGK-1 down-regulation may inactivate matrix metalloproteinase (MMP)-2, -9 expressions and inhibit hepatocellular carcinoma (HCC) migration. Antrodia cinnamomea is widely prescribed as an adjuvant to treat HCC in Taiwan. We aimed to investigate if ethanol extract of fruiting bodies of Antrodia cinnamomea (EEAC) and its active ingredients (i.e., zhankuic acid A, cordycepin, and adenosine) can modulate HCC cancer cells migration through ERp57 and PGK-1 and other molecular pathways such as PI3K/Akt and MAPK. ERp57 and PGK-1 siRNA were transfected into HCC to determine effects on MMP-2/-9 expressions and cell migration. We then examined the inhibitory effects of EEAC and its active ingredients on HCC migration and its related mechanisms including ERp57, PGK-1, PI3K/Akt, and MAPK signaling pathways. Down-regulation of ERp57 and PGK-1 by siRNA decreased MMP-2, -9 expressions and Transwell cell migration in HCC. Nontoxic EEAC markedly inhibited migration of HCC, and significantly inhibited activities and protein expressions of MMP-2 and -9, while the expression of the endogenous inhibitors (TIMP-1 and TIMP-2) of these proteins increased. Nontoxic EEAC and its active ingredients decreased ERp57, GLUD-1, GST-pi, and PGK-1 protein expressions. Finally, nontoxic EEAC inhibited the phosphorylated FAK, PI3K/Akt, and MAPK signaling. Our findings first indicate that EEAC and its ingredients effectively suppress HCC migration. Additionally, the molecular mechanisms appear to be mediated, in part, through the down-regulation of ERp57, PGK-1, MAPK, and PI3K/Akt.

MicroRNA-486-5p, which is downregulated in hepatocellular carcinoma, suppresses tumor growth by targeting PIK3R1.

Deregulated microRNAs and their roles in carcinogenesis and cancer progression have attracted much attention. In previous studies conducted in our laboratory, the Illumina Solexa massively parallel signature sequencing of miRNomes in nontumor and hepatocellular carcinoma (HCC) tissues revealed that miR-486-5p was significantly downregulated in HCC, but its role in HCC development remains unknown. In this study, miR-486-5p levels in HCC tissues and matched control tissues, and in seven HCC cell lines (QGY-7701, QGY-7703, QGY-7404, SMMC-7721, Huh7, HepG2, and PCL/PRF/5) and human normal liver cells (HL-7702), were tested by real-time quantitative RT-PCR. We found that the level of miR-486-5p was significantly decreased in HCC tissue and in all seven HCC cell lines. Overexpression of miR-486-5p markedly suppressed HCC cell proliferation, migration and invasion in vitro, and inhibited HCC growth in vivo. Mechanistically, miR-486-5p was confirmed to directly target PIK3R1 expression, thereby suppressing phosphatidylinositol 3-kinase-AKT pathway activation, by dual luciferase reporter assay and real-time quantitative RT-PCR and western blot analysis. In addition, PIK3R1 knockdown mimicked the effects of miR-486-5p overexpression by inhibiting HCC growth, migration, and invasion. Furthermore, correlation analysis, Kaplan-Meier estimates and Cox proportional hazard models showed an inverse correlation between miR-486-5p and PIK3R1, as well as a shorter time to recurrence after HCC resection, in patients with lower miR-486-5p expression. Hence, we conclude that miR-486-5p, which is frequently downregulated in HCC, inhibits HCC progression by targeting PIK3R1 and phosphatidylinositol 3-kinase-AKT activation.

Pathway crosstalk analysis of microarray gene expression profile in human hepatocellular carcinoma.

Liver cancer is the third most common cause of cancer death in the world. Hepatocellular carcinoma (HCC) is the main pathological types in liver cancer, which amounts to 70-85 % of primary liver cancer in the world and 90 % in China. The aim of this study was to establish a PPI network and a pathway crosstalk network to isolate important dysfunctional pathways which play an important role in the pathogenesis of HCC. System biology approach was used in this research. A PPI network was firstly built and then a dysfunctional crosstalk network of HCC related pathways was constructed. Several important significant dysfunctional crosstalk pathways were identified. Basal transcription factors (hsa03022), Glycerophospholipid metabolism (hsa00564) and Metabolism of xenobiotics by cytochrome P450 (hsa00980) were significantly interact with Pathway in cancer (hsa05200). Besides, pathway Axon guidance (hsa04360) was also dysfunctional crosstalk with Pathway in cancer (hsa05200). The crosstalks among these pathways reveal some evidence that the pathways closely cooperated and play important tasks in HCC progression. Besides, the pathway hsa04360 dysfunctional crosstalk with the hsa05200 indicates there would be a same mechanism for HCC invasion and migration.

GNAI3 inhibits tumor cell migration and invasion and is post-transcriptionally regulated by miR-222 in hepatocellular carcinoma

Guanine nucleotide binding protein, alpha inhibiting activity polypeptide 3 (GNAI3) is involved in many biological processes. However, its biological function in hepatocellular carcinoma (HCC) remains unclear. An immunohistochemical staining analysis revealed that GNAI3 protein was down-regulated in HCC compared to non-cancerous liver. Furthermore, transwell assays indicated that GNAI3 inhibits HCC cell migration and invasion. Using software predictions and experimental screening, we found that miR-222 could directly bind to GNAI3 mRNA and decrease GNAI3 protein expression in HCC cells. Moreover, miR-222 was up-regulated in HCC and negatively correlated with GNAI3 protein expression. These results indicated that down-regulation of GNAI3 might be caused by up-regulation of miR-222 in HCC. In conclusion, GNAI3 was down-regulated by miR-222 in HCC, and this deregulation promoted migration and invasion of HCC. These findings extended our insight into the complex molecular mechanisms underlying the invasion and metastasis of HCC and may provide new therapeutic targets.

Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma

The roles of alternatively activated (M2) macrophages on pro-tumour phenotypes have been well documented in many cancers except hepatocellular carcinoma (HCC). Considering their close relationship with chronic tissue injuries as well as enhanced tumour invasiveness and growth, we aimed to investigate the direct effects of M2 macrophages on HCC. M2 macrophages in 95 HCC clinical specimens were quantified using immunohistochemistry and quantitative PCR. The pro-tumour functions and the underlying molecular mechanisms of M2 macrophages in HCC were investigated in vivo and in an in vitro co-culture system. In the clinical study, high M2-specific CD163 (hazard ratio=2.693; p=0.043) and scavenger receptor A (hazard ratio=3.563; p=0.044) levels indicated poor prognosis and correlated with increased tumour nodules and venous infiltration in HCC patients. In an orthotopic model, the liver tumour volume was increased 3.26-fold (1.27 cm3±0.36) after M2 macrophage injection compared with the control (0.39 cm3±0.05) (p=0.032). An increased rate of lung metastasis was also found in the treatment group. In vitro, co-cultivation with M2 macrophages elevated the number of HCC cells (MHCC97L) and migration events by 1.3-fold and 3.2-fold, respectively (p<0.05). Strongly induced by MHCC97L, M2 macrophage-derived CCL22 was proven to enhance tumour migration capacities and correlate with venous infiltration in HCC patients. Increased epithelial-mesenchymal transition (EMT) via Snail activation in MHCC97L was found to be promoted by M2 macrophages and CCL22. M2 macrophages contribute to poor prognosis in HCC and promote tumour invasiveness through CCL22-induced EMT.

Prostaglandin E2 stimulates β1-integrin expression in hepatocellular carcinoma through the EP1 receptor/PKC/NF-κB pathway.

Prostaglandin E2 (PGE2) has been implicated in cell invasion in hepatocellular carcinoma (HCC), via increased β1-integrin expression and cell migration; however, the mechanism remains unclear. PGE2 exerts its effects via four subtypes of the E prostanoid receptor (EP receptor 1–4). The present study investigated the effect of EP1 receptor activation on β1-integrin expression and cell migration in HCC. Cell migration increased by 60% in cells treated with 17-PT-PGE2 (EP1 agonist), which was suppressed by pretreatment with a β1-integrin polyclonal antibody. PGE2 increased β1-integrin expression by approximately 2-fold. EP1 receptor transfection or treatment with 17-PT-PGE2 mimicked the effect of PGE2 treatment. EP1 siRNA blocked PGE2-mediated β1-integrin expression. 17-PT-PGE2 treatment induced PKC and NF-κB activation; PKC and NF-κB inhibitors suppressed 17-PT-PGE2-mediated β1-integrin expression. FoxC2, a β1-integrin transcription factor, was also upregulated by 17-PT-PGE2. NF-κB inhibitor suppressed 17-PT-PGE2-mediated FoxC2 upregulation. Immunohistochemistry showed p65, FoxC2, EP1 receptor and β1-integrin were all highly expressed in the HCC cases. This study suggested that PGE2 upregulates β1-integrin expression and cell migration in HCC cells by activating the PKC/NF-κB signaling pathway. Targeting PGE2/EP1/PKC/NF-κB/FoxC2/β1-integrin pathway may represent a new therapeutic strategy for the prevention and treatment of this cancer.

Rock2 promotes the invasion and metastasis of hepatocellular carcinoma by modifying MMP2 ubiquitination and degradation

Rho-associated coiled-coil-containing protein kinase 2 (Rock2) is a downstream effector of Rho that plays an important role in the tumorigenesis and progression of hepatocellular carcinoma (HCC). Matrix metalloproteinase 2 (MMP2) is a master regulator of tumor metastasis. In this study, we investigated the collections of Rock2 and MMP2 in HCCs and determined the potential role and molecular mechanism of Rock2 in MMP2-mediated invasiveness and metastasis. We found that Rock2 and MMP2 were markedly overexpressed in HCCs compared with the corresponding adjacent tissues, where a positive correlation in their expression was found. The knockdown of Rock2 significantly decreased MMP2 expression and inhibited the invasion and metastasis of HCC in vitro and in vivo. Additionally, the upregulation of MMP2 rescued the decreased migration and invasion induced by the knockdown of Rock2, whereas the knockdown of MMP2 decreased Rock2-enhanced HCC migration and invasion. Mechanistically, Rock2 stabilized MMP2 by preventing its ubiquitination and degradation. Together, our results link two drivers of invasion and metastasis in HCC and identify a novel pathway for MMP2 control.

MRC2 expression correlates with TGFβ1 and survival in hepatocellular carcinoma.

MRC2 (Mannose Receptor C Type 2) is a constitutively recycling endocytic receptor belonging to the mannose receptor family, which has been found to be closely involved with cancer metastasis. This study attempted to determine MRC2 expression on hepatocellular carcinoma (HCC) and its significance on postsurgical prognosis of HCCs. The expression of both MRC2 and transforming growth factor (TGFβ1) was detected in tumor tissues and adjacent liver tissues from 96 HCCs by immunohistochemistry staining, and it was found that MRC2 expression in HCC tissues was significantly higher than in adjacent liver tissues. HCCs with higher MRC2 expression had worse prognosis after liver resection. Univariate analysis showed that advanced TNM staging of HCC, higher Edmonson-Steiner classification, intrahepatic metastases, portal vein invasion, higher MRC2 and higher TGFβ1 were the poor prognostic factors. Furthermore, multivariate analysis revealed that intrahepatic metastases, higher MRC2 and higher TGFβ1 were the independent prognostic factors. TGFβ1 treatment up-regulated MRC2 expression, cell migration and invasion of Huh7 cells notably. In addition, knockdown of MRC2 repressed the effect of TGFβ1 on cell migration and invasion. These data suggest that MRC2 overexpression predicts poor prognosis of HCCs after liver resection and MRC2 potentially contributed to TGFβ1-driven up-regulation of cell migration and invasion in HCC.

A cell-surface β-hydroxylase is a biomarker and therapeutic target for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a poor prognosis as a result of widespread intra- and extrahepatic metastases. There is an urgent need to understand signaling cascades that promote disease progression. Aspartyl-(asparaginyl)-β-hydroxylase (ASPH) is a cell-surface enzyme that generates enhanced cell motility, migration, invasion, and metastatic spread in HCC. We hypothesize that inhibition of its enzymatic activity could have antitumor effects. Small molecule inhibitors (SMIs) were developed based on the crystal structure of the ASPH catalytic site followed by computer-assisted drug design. Candidate compounds were tested for inhibition of β-hydroxylase activity and selected for their capability to modulate cell proliferation, migration, invasion, and colony formation in vitro and to inhibit HCC tumor growth in vivo using orthotopic and subcutaneous murine models. The biological effects of SMIs on the Notch signaling cascade were evaluated. The SMI inhibitor, MO-I-1100, was selected because it reduced ASPH enzymatic activity by 80% and suppressed HCC cell migration, invasion, and anchorage-independent growth. Furthermore, substantial inhibition of HCC tumor growth and progression was observed in both animal models. The mechanism(s) for this antitumor effect was associated with reduced activation of Notch signaling both in vitro and in vivo. These studies suggest that the enzymatic activity of ASPH is important for hepatic oncogenesis. Reduced β-hydroxylase activity generated by the SMI MO-I-1100 leads to antitumor effects through inhibiting Notch signaling cascade in HCC. ASPH promotes the generation of an HCC malignant phenotype and represents an attractive molecular target for therapy of this fatal disease.

Mannose-mediated inhibitory effects of PA-MSHA on invasion and metastasis of hepatocellular carcinoma via EGFR/Akt/IκBβ/NF-κB pathway.

Elevation of high-mannose glycans is a common feature of malignant cells and has been suggested to be the basis for alternative cancer therapy for several years. Here we want to investigate the antitumour effect of pseudomonas aeruginosa-mannosesensitive haemagglutinin (PA-MSHA), a genetically engineered heat-inactivated PA strain with mannose-sensitive binding activity, on hepatocellular carcinoma (HCC). Tumourigenicity and metastatic potentials of HCC were studied after PA-MSHA treatment by utilizing the in vitro/in vivo model of HCC. Expression of apoptosis-associated proteins and epithelial-mesenchymal transition (EMT) related genes were evaluated, and possible signalling pathways involved were investigated. PA-MSHA induced significant cell proliferation inhibition and cell cycle arrest of HCC through decreasing the levels of cyclins D1, cyclins E, CDK2, CDK4, proliferating cell nuclear antigen (PCNA), and increasing the level of p21 and p27. Moreover, PA-MSHA suppressed the invasion, migration and adhesion of HCC through inhibiting epithelial-mesenchymal transition (EMT). PA-MSHA also inhibited EGFR/Akt/IκBβ/NF-κB pathway and overexpression of NF-κB significantly abrogated PA-MSHA induced EMT inhibition. In addition, competitive inhibition of the mannose binding activity of PA-MSHA by D-mannose significantly blocked its effect on cell cycle arrest and EMT. PA-MSHA also abrogated lung metastasis of HCC and significantly inhibited tumour growth in the in vivo study. Our study demonstrated the essential role of EGFR/Akt/IκBβ/NF-κB pathway in the inhibitory effect of PA-MSHA on invasion and metastasis of HCC through suppressing EMT, and revealed an attractive prospect of PA-MSHA as a novel candidate agent in the treatment of HCC.

Sox17 inhibits hepatocellular carcinoma progression by downregulation of KIF14 expression.

Sox17, an antagonist of canonical Wnt/β-catenin signaling, inhibits several malignant carcinogenesis and progression. However, little is known about Sox17 in hepatocellular carcinoma (HCC). Here, we found that Sox17 is downregulated in HCC tissue. Furthermore, Sox17 inhibits cell proliferation and migration in HCC. KIF14, a member of kinesin superfamily protein (KIFs), is an oncogene in a variety of malignant tumors including HCC. We demonstrated that Sox17 is negatively related to KIF14 expression in HCC tissue and Sox17 inhibits HCC cell proliferation and migration by transcriptional downregulation of KIF14 expression. Our results may provide a strategy for blocking HCC carcinogenesis and progression.

The effects of the CCR6/CCL20 biological axis on the invasion and metastasis of hepatocellular carcinoma.

Chemokines and their receptors have recently been shown to play major roles in cancer metastasis. Chemokine receptor 6 (CCR6) and its ligand, CCL20, were highly expressed in a variety of human cancers. In our present study, we aimed to clarify whether CCR6/CCL20 was correlated with the migration of hepatocellular carcinoma (HCC). RT-PCR and Western blot results showed that CCR6 was overexpressed in different invasive potential HCC cell lines (p < 0.05), while the expression of CCL20 had no obvious difference (p > 0.05). CCR6 was suppressed by siRNA in HCCLM6, and then the biological behaviors of HCCLM6 cells were observed. The results showed that the CCR6/CCL20 biological axis increased the capacity of proliferation and adhesion, as well as the chemotactic migration and the level of cytokines related to degraded extracellular matrix. In conclusion, these findings indicate that CCR6 indeed participates in regulating the migration and invasion of HCC, and it might become a prognostic factor of HCC.

S1P receptor‐1 and USP4 induced by microRNA‐148a deregulation facilitate liver cancer progression (766.1)

Hepatocellular carcinoma (HCC) is frequently aggressive. MicroRNAs (miRNAs) emerge as key contributors to tumor progression. In the present study, we report that deregulation of miR‐148a causes the induction of sphingosine 1‐phosphate receptor 1 (S1P1) and ubiquitin specific protease 4 (USP4) in association with HCC progression. In patients with HCC, S1P1 and USP4 were both up‐regulated with miR‐148a deregulation. Moreover, decrease of miR‐148a discriminated microvascular invasion of HCC, the overall survival and recurrence free survival rates of the patients. In cell models, miR‐148a was repressed in mesenchymal‐typed liver‐tumor cells, which facilitated S1P1 and USP4 induction, as shown by the assays using mimic, antisense oligonucleotide and 3’‐UTR reporter. S1P1 and USP4 levels were markedly increased in liver‐tumor cells having a mesenchymal phenotype. S1P1 over‐expression enhanced ERK1/2 activation, increasing proliferation and migration of liver‐tumor cells, which was attenuated by miR‐148a mimic transfection. Decrease of miR‐148a additionally caused USP4 induction, which may account for TGFβ1‐dependent epithelial‐mesenchymal transition (EMT) in HCC. In summary, S1P1 and USP4 induced by miR‐148a deregulation may facilitate HCC growth and migration in microenvironments, and contribute to cancer progression.

Anti-miR-197 inhibits migration in HCC cells by targeting KAI 1/CD82

AimTo investigate the metastatic effects and mechanisms of miR-197 in hepatocellular carcinoma (HCC). Methods and resultsThe levels of miR-197 increased in HCC cells and tissues compared with a normal hepatic cell line (LO2) and adjacent nontumorous liver tissues, respectively. miR-197 expression negatively correlated with CD82 mRNA expression in these cell lines and tissues. Dual luciferase reporter assay and Western blot confirmed a direct interaction between miR-197 and CD82 3′UTR sequences. After miR-197 was silenced in HCC cells, CD82 expression increased. In the presence of human hepatocyte growth factor (HGF), cells silenced for anti-miR-197 exhibited elongated cellular tails and diminished lamellipodia due to reductions in both ROCK activity and the levels of Rac 1 protein. Downregulation of miR-197 along with the upregulation of CD82 in HCC cells resulted in the inhibition of HCC migration and invasion in vitro and in vivo. ConclusionTaken together, these data suggest that anti-miR-197 suppresses HCC migration and invasion by targeting CD82. The regulation of the miR-197/CD82 axis could be a novel therapeutic target in future HCC effective therapy.

Overexpression of PITPNM3 promotes hepatocellular carcinoma cell metastasis

A previous study indicated that C–C chemokine (C–C motif) ligand 18 (CCL18) is capable of inducing tumor cell invasion and metastasis by interacting with receptor membrane-associated phosphatidylinositol transfer protein 3 (PITPNM3) in breast cancer cells. The present study aims to investigate the correlation between the PITPNM3 expression and metastasis in hepatocellular carcinoma (HCC). Real-time quantitative polymerase chain reaction and Western blot were performed to detect the expression pattern of PITPNM3 in patient samples and HCC cell lines. Wound-healing and transwell chamber assays were performed to assess the migration and invasiveness of HCC cells, and the activation of the signaling protein downstream of PITPNM3 was also detected by Western blot and immunofluorescence. The results revealed that PITPNM3 was upregulated in HCC tissue compared to matched normal liver tissue. Silencing the expression of PITPNM3 by specific siRNAs markedly attenuated the invasive and metastatic abilities of HCC cells, whereas the upregulation of PITPNM3 significantly increased HCC cell mobility. Furthermore, inhibiting the expression of PITPNM3 suppressed the activation of Pyk2, FAK, and Src, while overexpression of PITPNM3 enhanced the phosphorylation of FAK and Src in HCC cells. Besides, suppression of Pyk2 can also impair the clustering of integrin. These results imply that PITPNM3 is a vital determinant of HCC migration and invasion.

PAF-receptor antagonists reduce HCC progression blocking cancer cell proliferation and migration

Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there is no effective treatment for advance stage HCC. PAF-receptor antagonists WEB-2086 and WEB-2170 (WEBs) have been previously shown to induce differentiation, growth arrest and massive apoptosis in in murine and human leukemia cells.

Hepatitis B virus X protein mutant HBxΔ127 promotes proliferation of hepatoma cells through up-regulating miR-215 targeting PTPRT

The mutant of virus is a frequent event. Hepatitis B virus X protein (HBx) plays a vital role in the development of hepatocellular carcinoma (HCC). Therefore, the identification of potent mutant of HBx in hepatocarcinogenesis is significant. Previously, we identified a natural mutant of the HBx gene (termed HBxΔ127). Relative to wild type HBx, HBxΔ127 strongly enhanced cell proliferation and migration in HCC. In this study, we aim to explore the mechanism of HBxΔ127 in promotion of proliferation of hepatoma cells. Our data showed that both wild type HBx and HBxΔ127 could increase the expression of miR-215 in hepatoma HepG2 and H7402 cells. However, HBxΔ127 was able to significantly increase miR-215 expression relative to wild type HBx in the cells. We identified that protein tyrosine phosphatase, receptor type T (PTPRT) was one of the target genes of miR-215 through targeting 3′UTR of PTPRT mRNA. In function, miR-215 was able to promote the proliferation of hepatoma cells. Meanwhile anti-miR-215 could partially abolish the enhancement of cell proliferation mediated by HBxΔ127 in vitro. Knockdown of PTPRT by siRNA could distinctly suppress the decrease of cell proliferation mediated by anti-miR-215 in HepG2-XΔ127/H7402-XΔ127 cells. Moreover, we found that anti-miR-215 remarkably inhibited the tumor growth of hepatoma cells in nude mice. Collectively, relative to wild type HBx, HBxΔ127 strongly enhances proliferation of hepatoma cells through up-regulating miR-215 targeting PTPRT. Our finding provides new insights into the mechanism of HBx mutant HBxΔ127 in promotion of proliferation of hepatoma cells.