Hepatocellular Carcinoma Migration Research Articles

The Down-Regulation of SUZ12 Accelerates the Migration and Invasion of Liver Cancer Cells via Activating ERK1/2 Pathway.

The suppressor of zest 12 (SUZ12), an essential subunit of the transcription polycomb repressive complex 2 (PRC2), has been found to be involved in HBV X-induced oncogenic transformation in hepatocellular carcinoma (HCC). However, the specific function of SUZ12 has not yet been determined in the pathogenesis of migration and invasion of HBV-associated HCC. Here, our results showed that SUZ12 was significantly down-regulated in HBV-related HCC tissues compared with adjacent non-tumor tissues by immunohistochemical and Western blot assays. The 5-years survival rate was worse in patients with low expression level of SUZ12. SUZ12 silencing increased the migration and invasion of HCC cells, and its overexpression impaired HCC cells migration and invasion. Knockdown of SUZ12 activated ERK1/2 pathway and increased MMP9 (matrix metallopeptidase 9) and MMP2 (matrix metallopeptidase 2) expression, whereas SUZ12 overexpression had opposite effects. Specific ERK1/2 inhibitor (SCH772984) significantly decreased HCC cells migration and invasion caused by SUZ12 shRNA. Thus, the liver cancer-down-regulated SUZ12 accelerated the invasion and metastasis of HCC cells. These effects might be associated with deregulation of SUZ12 activating ERK1/2, MMP2 and MMP9 in HCC cells.

MicroRNA-1271 functions as a potential tumor suppressor in hepatitis B virus-associated hepatocellular carcinoma through the AMPK signaling pathway by binding to CCNA1.

Hepatocellular carcinoma (HCC) is mainly associated with hepatitis B virus (HBV) infection and characterized by metastasizing and infiltrating adjacent and distant tissues. Notably, microRNA-1271 (miR-1271) is a tumor suppressor in various cancers. Therefore, we evaluate the ability of miR-1271 to influence cell proliferation, migration, invasion, and apoptosis in HBV-associated HCC through the Adenosine monophosphate-activated protein kinase (AMPK) signaling pathway via targeting CCNA1. HBV-associated HCC and adjacent normal tissues were collected to identify the expression of miR-1271 and CCNA1. To verify the relationship between miR-1271 and CCNA1, we used bioinformatics prediction and the dual-luciferase reporter gene assay. The effects of miR-1271 on HBV-associated HCC cell behaviors were investigated by treatment of the miR-1271 mimic, the miR-1271 inhibitor, or small interfering RNAagainst CCNA1. The HBV-DNA quantitative assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromid assay, scratch test, transwell assay, and flow cytometry were used to detect HBV-DNA replication, cell proliferation, invasion, migration, and apoptosis. MiR-1271 showed a low expression, whereas CCNA1 showed a high expression in HBV-associated HCC tissues. We identified that miR-1271 targeted and negatively regulated CCNA1. Upregulated miR-1271 and downregulated CCNA1 inhibited the HBV-associated HCC cell HBV-DNA replication, proliferation, migration, and invasion, while accelerating apoptosis by activating the AMPK signaling pathway. MiR-1271 promotes the activation of the AMPK signaling pathway by binding to CCNA1, whereby miR-1271 suppresses HBV-associated HCC progression. This study points to a potential therapeutic approach of downregulation of miR-1271 in HBV-associated HCC treatment.

LncRNA CRNDE promotes the epithelial-mesenchymal transition of hepatocellular carcinoma cells via enhancing the Wnt/β-catenin signaling pathway.

Colorectal neoplasia differentially expressed (CRNDE) is a significantly upregulated long noncoding RNA in hepatocellular carcinoma (HCC). CRNDE could promote cell proliferation, migration, and invasion, while its molecular mechanisms were still largely unclear. In this study, we investigated the expression and function of CRNDE. CRNDE was significantly upregulated in tumor tissues compared with adjacent normal tissues. In vitro, we revealed that knockdown of CRNDE inhibited cell proliferation, migration, and cell invasion capacities in HCC. Animal studies indicated that CRNDE knockdown represses both growth and metastasis of HCC tumors in vivo. Moreover, knockdown of CRNDE suppressed the cell epithelial‐mesenchymal transition (EMT) process by increasing the expression of E‐cadherin and ZO‐1, whereas, decreasing the expression of N‐cadherin, slug, twist, and vimentin in HCC cells. We also revealed that knockdown of CRNDE suppressed the Wnt/β‐catenin signaling in HCC. Thus, CRNDE could modulate EMT of HCC cells and knockdown of CRNDE impaired the mesenchymal properties. CRNDE increased invasion of HCC cells might be through activating the Wnt/β‐catenin signaling pathway.

Uridine-cytidine kinase 2 promotes metastasis of hepatocellular carcinoma cells via the Stat3 pathway.

IntroductionUridine-cytidine kinase 2 (Uck2) has been demonstrated to activate antitumor prodrugs and regulate chemosensitivity in cancer cells. However, the expression and function of Uck2 in hepatocellular carcinoma (HCC) remain unknown. In this study, we were the first to systematically elucidate the role of Uck2 in HCC.Patients and methodsUck2 gene expression was queried between normal liver tissues and HCC in a web-based data mining platform (www.oncomine.org). Uck2 gene expression in tissue microarray was determined by immunohistochemical staining. The clinical and prognostic significance of Uck2 expression was statistically analyzed. Stable cell lines with increased Uck2 expression were established using lentivirus-based vectors, and RNAi technology was used to transiently downregulate Uck2 expression. Cell migration and invasion were assessed by using wound-healing and transwell assays, respectively. mRNA and protein expression levels were determined using quantitative real-time PCR and Western blotting, respectively.ResultsWe report the upregulation of Uck2 expression in HCC tissues. We explored the relationship between Uck2 levels and the clinicopathological features of HCC patients. High Uck2 notably correlated with early recurrence and poor prognosis in HCC patients. Uck2 expression in HCC cell lines regulated the cell migration and invasion capacities in vitro. The stable overexpression of Uck2 in Bel-7402 cells promoted their metastasis ability in vivo. Furthermore, the Uck2 upregulation increased the MMP2/9 expression and activated the Stat3 signaling pathway. In addition, WP1066, a Stat3 inhibitor, neutralized the effects of Uck2 on the MMP2/9 expression and the migration and invasion capacities of HCC cells.ConclusionOur data suggest that Uck2 promotes HCC cell migration and invasion via the Stat3 signaling pathway and might be a novel potential target in HCC therapy.

Long non-coding RNA CRNDE promotes the proliferation, migration and invasion of hepatocellular carcinoma cells through miR-217/MAPK1 axis.

Hepatocellular carcinoma (HCC) is an invasive malignant tumour and the second major cause of cancer‐related deaths over the world. CRNDE and miR‐217 are non‐coding RNAs which play critical roles in cell growth, proliferation, migration. Mitogen‐activated protein kinase 1 (MAPK1) also participates in cancer cell process. Hence, this study aimed at investigating the effect of CRNDE on migration and invasion of HCC and figuring out the role of miR‐217 and MAPK1 in this process. The overexpression of CRNDE was demonstrated by a microarray‐based lncRNA profiling study. CRNDE expression in HCC was verified by qRT‐PCR. MTT assay and BrdU staining were applied to detect cell proliferation level. Transwell assay was utilized to examine cell migration and invasiveness abilities. Wound healing assay was performed for further exploration of cell migration capacity. MiR‐217 was predicted by bioinformatics. The dual luciferase reporter assay was performed to corroborate the targeting relationship between CRNDE, miR‐217 and MAPK1. MAPK1, the downstream target of miR‐217, was predicted using bioinformatics and was further confirmed by qRT‐PCR and Western blot. The interaction between CRNDE, miR‐217 and MAPK1 was studied by qRT‐PCR, Western blot, MTT, BrdU, transwell assay and wound healing assay. CRNDE was up‐regulated in HCC tissues and HCC cell lines. The high expression of CRNDE facilitated cell proliferation, migration and invasion, while the inhibited one affected on the contrary. MiR‐217, negatively correlated with CRNDE expression, was the target of CRNDE and was more lowly expressed in HCC. With the high expression of miR‐217, HCC cell proliferation, migration and invasion were suppressed. MAPK1, the possible target of miR‐217, was negatively correlated with miR‐217 but positively correlated with CRNDE and had the same effect in HCC formation process as CRNDE. Long non‐coding RNA CRNDE promotes the proliferation, migration and invasion of HCC cells through miR‐217/MAPK1 axis.

RETRACTED ARTICLE: miR-665 promotes hepatocellular carcinoma cell migration, invasion, and proliferation by decreasing Hippo signaling through targeting PTPRB

Growing evidence suggests that aberrant microRNA (miRNA) expression contributes to hepatocellular carcinoma (HCC) development and progression. However, the potential role and mechanism of miR-665 in the progression of liver cancer remains largely unknown. Our current study showed that miR-665 expression was upregulated in HCC cells and tissues. High expression of miR-665 exhibited more severe tumor size, vascular invasion and Edmondson grading in HCC patients. Gain- or loss-of-function assays demonstrated that miR-665 promoted cell proliferation, migration, invasion, and the epithelial–mesenchymal transition (EMT) of HCC cells in vitro and in vivo. Tyrosine phosphatase receptor type B (PTPRB) was downregulated in HCC tissues, and was negatively correlated with miR-665 expression. Through western blotting and luciferase reporter assay, PTPRB was identified as a direct downstream target of miR-665. Restoration of PTPRB reverses the effects of miR-665 on HCC migration, invasion, and cell proliferation. A mechanistic study showed that PTPTRB mediated the functional role of miR-665 through regulation of the Hippo signaling pathway. In conclusion, our results suggested that miR-665 was a negative regulator of the PTPRB and could promote tumor proliferation and metastasis in HCC through decreasing Hippo signaling pathway activity, which can be a potential target for HCC treatment.

Long noncoding RNA DGCR5 represses hepatocellular carcinoma progression by inactivating Wnt signaling pathway.

Increasing studies have indicated that long noncoding RNAs (lncRNAs) exert important roles in hepatocellular carcinoma (HCC). Therefore, it is of great significance to identify the dysregulated lncRNAs in HCC. According to the previous reports, it has been suggested that DiGeorge syndrome critical region gene 5 (DGCR5) might participate in HCC and can serve as potential biomarker for HCC. In our current study, we concentrated on the biological function and roles of lncRNA-DGCR5 in HCC. It was indicated that DGCR5 was decreased in HCC tissues and HCC cells including HepG2, Hep3B, MHCC-97L, SNU-449, and SNU-182 cells compared with the normal human liver cell line LO2. Overexpression of DGCR5 was able to restrain HCC growth, migration, and invasion capacity in HepG2 and SNU-449 cells. In addition, whether lncRNA-DGCR5 can regulate Wnt/β-catenin pathway during HCC progression is unclear. In our study, it was found that upregulation of DGCR5 inactivated Wnt signaling pathway through inhibiting β-catenin, cyclin D1 and increasing GSK-3β levels. Subsequently, in vivo tumor xenografts were established using HepG2 cells to investigate the function of DGCR5 in HCC development. Inconsistent with the in vitro findings, increase of DGCR5 dramatically suppressed HCC tumor progression in vivo. Taken these together, it was uncovered in our research that DGCR5 could play tumor suppressive role by targeting Wnt signaling in HCC progression.

MiR-1306–3p targets FBXL5 to promote metastasis of hepatocellular carcinoma through suppressing snail degradation

This study aimed to elucidate the effect of miR-1306–3p on metastasis of hepatocellular carcinoma (HCC) and potential mechanism involved. miR-1306–3p promoted migration and invasion of HCC in vivo and in vitro. Moreover, miR-1306–3p inhibited snail to enhance its expression via directly targeting FBXL5, thus inducing the epithelial-mesenchymal transition (EMT) in HCC. Intriguingly, miR-1306–3p expression was transcriptionally enhanced by FoxM1. Consistently, miR-1306–3p was upregulated in HCC compared with paracarcinoma and correlated with poor prognosis of HCC patients. Our researches suggest that miR-1306–3p is a tumor enhancer in regulating of HCC metastasis, and miR-1306–3p may be clinically utilized as a factor for the clinical diagnosis and prognosis of HCC.

Integrin α6 as an invasiveness marker for hepatitis B viral X-driven hepatocellular carcinoma.

Hepatitis B virus (HBV) accounts for more than 60% of hepatocellular carcinoma (HCC) cases. However, there is limited information about the features of HBV-driven HCC that differentiate it from other types of HCC. The aim of this study is to find a gene specific to HBV-driven HCC and understand its role during tumorigenesis. The differences in gene expression patterns were analyzed among patients with hepatitis virus-unrelated liver cirrhosis, and hepatitis C virus- and HBV-driven HCC. Genes expressed only in HBV patients were compared to genes of transgenic mice expressing hepatitis B viral X gene. Integrin α6 was commonly overexpressed in both HBV-driven HCC patients and transgenic mice expressing viral X. This gene's activation induced overexpression of integrin α6, as well as formation of integrins α6β1 and α6β4, without changing the expression of non-integrin laminin receptors. Suppression of integrin α6 caused significant inhibition of tumor migration in vitro. This study found a significant association between HBV and integrin α6, which may be responsible for early migration and invasion of HCC. Thus, integrin α6 is a predictive marker for tumor recurrence and invasiveness of HBV-driven HCC.

MicroRNA-766-3p Inhibits Tumour Progression by Targeting Wnt3a in Hepatocellular Carcinoma.

Recent studies have indicated that microRNAs (miRNAs) play an important role in hepatocellular carcinoma (HCC) progression. In this study, we showed that miR-766-3p was decreased in approximately 72% of HCC tissues and cell lines, and its low expression level was significantly correlated with tumour size, TNM stage, metastasis, and poor prognosis in HCC. Ectopic miR-766-3p expression inhibited HCC cell proliferation, colony formation, migration and invasion. In addition, we showed that miR-766-3p repressed Wnt3a expression. A luciferase reporter assay revealed that Wnt3a was a direct target of miR-766-3p, and an inverse correlation between miR-766-3p and Wnt3a expression was observed. Moreover, Wnt3a up-regulation reversed the effects of miR-766-3p on HCC progression. In addition, our study showed that miR-766-3p up-regulation decreased the nuclear β-catenin level and expression of Wnt targets (TCF1 and Survivin) and reduced the level of MAP protein regulator of cytokinesis 1 (PRC1). However, these effects of miR-766-3p were reversed by Wnt3a up-regulation. In addition, PRC1 up-regulation increased the nuclear β-catenin level and protein expression of TCF1 and Survivin. iCRT3, which disrupts the β-catenin-TCF4 interaction, repressed the TCF1, Survivin and PRC1 protein levels. Taken together, our results suggest that miR-766-3p down-regulation promotes HCC cell progression, probably by targeting the Wnt3a/PRC1 pathway, and miR-766-3p may serve as a potential therapeutic target in HCC.

Caveolin enhances hepatocellular carcinoma cell metabolism, migration, and invasion in vitro via a hexokinase 2-dependent mechanism.

The development and progression of hepatocellular carcinoma (HCC) have been associated with abnormal cellular metabolism. Gene Expression Profiling Interactive Analysis RNA sequencing data revealed caveolin-1 (CAV-1) and hexokinase 2 (HK2) messenger RNA (mRNA) were significantly upregulated in human HCC compared with normal tissues, and high HK2 expression was associated with significantly poorer overall survival in HCC ( p < 0.05). CAV-1 and HK2 mRNA and protein expression were upregulated and positively correlated in 42 fresh human HCC tissues compared with tumor-adjacent normal tissues. Overexpression of CAV-1 or HK2 in SMMC-7721 and HepG2 HCC cells enhanced glucose and lactate metabolism and increased cell migration and invasion in transwell assays; knocking down CAV-1 or HK2 had the opposite effects. Overexpression of CAV-1 increased HK2 expression; overexpression of HK2 did not affect CAV-1 expression. Knocking down HK2 partially reversed the ability of CAV-1 to promote cellular metabolism, invasion, and migration in HCC, indicating CAV-1 enhances glycolysis, invasion, and metastasis in HCC cells via HK2-dependent mechanism. Further studies of the function and relationship between CAV-1 or HK2 expression are warranted to explore the potential of these proteins as metabolic targets for the treatment of HCC.

Establishment and characterization of McA-RH7777 cells using virus-mediated stable overexpression of enhanced green fluorescent protein.

Hepatocellular carcinoma (HCC), the most common primary tumor of the liver, has a poor prognosis, rapid progression. The aim of the current study was to establish a stable lentiviral expression vector for enhanced green fluorescent protein (EGFP) and to evaluate biological characteristics on HCC growth and migration following transfection of HCC cells with EGFP. McA-RH7777 cells were transfected with EGFP overexpression lentiviral vector. Cell activity and mobility were monitored with a Cell-IQ Analyzer. Transwell assays were performed to detect invasiveness and flow cytometry was performed for cell cycle analysis. A subcutaneous tumor rat model was established to analyze the stability of fluorescent protein expression. The result suggested no significant differences between wild-type and EGFP-overexpressing McA-RH7777 cells with regards to cell proliferation, activity, mobility, invasiveness and cell cycle. Green fluorescence was detected over 108 days of culturing. The subcutaneous tumor rat model demonstrated that EGFP expression had no influence on tumor growth and long-term expression was stable. The stable EGFP expression of the HCC transplanted tumor rat model may share biological characteristics with human liver cancer. The model established in the current study may be suitable for various applications, including research focusing on liver cancer metastasis and recurrence, interventional therapy, imaging diagnosis and drug screenings.

MiR-190 promotes HCC proliferation and metastasis by targeting PHLPP1

miRNAs regulate gene expression and enable clinicians to distinguish between benign and malignant tissues in cancers. PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1) is known to be a tumour suppressor. A lentiviral overexpression system was used to stably express miR-190, leading to the enhancement of hepatocellular carcinoma (HCC) proliferation and metastasis as a result of inhibited PHLPP1 expression. The results showed that stable miR-190 expression increased the expression of EMT-related proteins (Snail and TCF8/ZEB1) as well as the phosphorylation of Akt at Ser473 and the expression of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1). However, restoring PHLPP1 expression counteracted the effects of miR-190 on HCC proliferation, migration and invasion. The results of the animal experiments showed that miR-190 improved the HepG2 cell tumour formation and lung metastasis ability. Stable miR-190 overexpression leads to the downregulation of PHLPP1 protein expression. miR-190 has potential as a target in the treatment and diagnosis of HCC.

Crosstalk between hepatic tumor cells and macrophages via Wnt/\u03b2-catenin signaling promotes M2-like macrophage polarization and reinforces tumor malignant behaviors

Tumor-associated macrophages (TAMs) are a major component of tumor microenvironment (TME) and play pivotal roles in the progression of hepatocellular carcinoma (HCC). Wnt signaling is evolutionarily conserved and participates in liver tumorigenesis. Several studies have shown that macrophage-derived Wnt ligands can activate Wnt signaling in tumor cells. However, whether Wnt ligands secreted by tumor cells can trigger Wnt signaling in macrophages is still elusive. In this study, we first verified that canonical Wnt/β-catenin signaling was activated during monocyte-to-macrophage differentiation and in M2-polarized macrophages. Knockdown of β-catenin in M2 macrophages exhibited stronger antitumor characteristics when cocultured with Hepa1-6 HCC cells in a series of experiments. Activation of Wnt signaling promoted M2 macrophage polarization through c-Myc. Moreover, co-culturing naïve macrophages with Hepa1-6 HCC cells in which Wnt ligands secretion was blocked by knockdown of Wntless inhibited M2 polarization in vitro. Consistently, the growth of HCC tumor orthotopically inoculated with Wntless-silenced Hepa1-6 cells was impeded, and the phenotype of M2-like TAMs was abrogated due to attenuated Wnt/β-catenin signaling in TAMs, leading to subverted immunosuppressive TME. Finally, we confirmed the correlation between M2 macrophage polarization and nuclear β-catenin accumulation in CD68+ macrophages in human HCC biopsies. Taken together, our study indicates that tumor cells-derived Wnt ligands stimulate M2-like polarization of TAMs via canonical Wnt/β-catenin signaling, which results in tumor growth, migration, metastasis, and immunosuppression in HCC. To block Wnts secretion from tumor cells and/or Wnt/β-catenin signal activation in TAMs may be potential strategy for HCC therapy in future.

IFITM3 promotes hepatocellular carcinoma invasion and metastasis by regulating MMP9 through p38/MAPK signaling.

Interferon‐induced transmembrane protein 3 (IFITM3) has been shown to be overexpressed in multiple cancers. However, the role of IFITM3 in metastasis of hepatocellular carcinoma (HCC) is still poorly understood. In this study, we showed that IFITM3 was frequently overexpressed in HCC tissues compared with adjacent nontumor tissues. Overexpression of IFITM3 was significantly correlated with tumor metastasis and poor prognosis in HCC. Knockdown of IFITM3 dramatically decreased MMP9 expression and inhibited the invasion and metastasis of HCC in vitro and in vivo. Moreover, the upregulation of MMP9 rescued the decreased migration and invasion induced by the knockdown of IFITM3, whereas the knockdown of MMP9 decreased IFITM3‐enhanced HCC migration and invasion. Mechanistically, we found that IFITM3 regulates MMP9 expression through the p38/MAPK pathway. Taken together, we identified a novel IFITM3–p38/MAPK–MMP9 regulatory circuitry, the dysfunction of which drives invasive and metastatic character in HCC.

MiR-185 inhibits cell migration and invasion of hepatocellular carcinoma through CDC42.

Hepatocellular carcinoma (HCC) is a primary liver cancer with high incidence and mortality. miR-185, a microRNA with appriximately 22-28 nucleotides, was reported to be involved in many cancers. The potential mechanism of miR-185 on HCC through cell division cycle 42 (CDC42) was investigated. RT-qPCR was used to measure the RNA level of miR-185 and CDC42 in HCC tissues and cells. The dual luciferase reporter assay was used to verify whether CDC42 was a target gene for miR-185. Transwell assay was employed to detect the ability of migration and invasion to change miR-185. miR-185 expression was low in HCC and negatively correlated with CDC42. miR-185 inhibited HCC migration, invasion and miR-185 low expression predicted poor prognosis. CDC42 was predicted to be a target gene for miR-185, and regulated by miR-185. miR-185 suspressed the ability of cell migration and invasion through CDC42 in HCC. In conclusion, miR-185 suspressed migration and invasion of HCC cells by directly targeting CDC42. It is suggested that miR-185/CDC42 axis may present a novel target for HCC treatment.

Downregulated Trophinin-Associated Protein Plays a Critical Role in Human Hepatocellular Carcinoma Through Upregulation of Tumor Cell Growth and Migration.

Trophinin-associated protein (TROAP) was a protein first identified to mediate the process of embryo transplantation and later found to be involved in microtubule regulation. However, little is known about the role of TROAP in hepatocellular carcinoma (HCC). In the present study, we reported that both TROAP mRNA and protein expressions were downregulated in human HCC samples as well as cell lines. A high level of TROAP was associated with small tumor size (p < 0.05), minor tumor nodules (p < 0.01), and mild vein invasion (p < 0.05). We further constructed in vitro TROAP depletion and overexpression HCC cell models. TROAP depletion significantly enhanced the proliferation and colony formation abilities, whereas TROAP overexpression had an inhibitory effect on the growth of HCC cells. The G1/S phase arrest by TROAP overexpression correlated with increased cell cycle inhibitors p21 and p27, and declined cell cycle promoting kinase complex CDK6/cyclin D1. Depressed TROAP expression enhanced the migration ability, while the opposite influence was observed in TROAP-overexpressed HCC cells. Taken together, these results indicate that TROAP suppresses cellular growth and migration in HCC. This discovery will further our understanding of the pathogenic mechanisms of human HCC.

DDX39 promotes hepatocellular carcinoma growth and metastasis through activating Wnt/\u03b2-catenin pathway

Hepatocellular carcinoma (HCC) is the third leading cause of cancer related death worldwide; however, the molecular mechanisms regulating HCC progression remain largely unknown. In this study, we determined the role of DDX39 which a DEAD-box RNA helicase in HCC progression, and found DDX39 was upregulated in HCC tissues and cells, DDX39 expression was positive correlated with advanced clinical stage, survival analysis showed patients with high-DDX39 levels had poor outcome, it was an independent prognostic factor. Functional analysis revealed that DDX39 overexpression promoted HCC cell migration, invasion, growth, and metastasis, DDX39 knockdown inhibited HCC cell migration, invasion, growth, and metastasis. Mechanism analysis suggested DDX39 overexpression increased β-catenin expression in nucleus and increased Wnt/β-catenin pathway target genes levels, while DDX39 knockdown reduced this effect. Knockdown of Wnt/β-catenin pathway co-activators TCF4 and LEF1 in DDX39 overexpressing HCC cells inhibited Wnt/β-catenin pathway target genes. The invasion ability was also reduced, confirming DDX39 regulates HCC progression by activating Wnt/β-catenin pathway. In conclusion, we found DDX39 is a target and prognostic factor for HCC, and promotes HCC migration, invasion, growth, and metastasis by activating Wnt/β-catenin pathway.

Visfatin increases miR-21 to promote migration in HCC

Hepatocellular carcinoma (HCC) is a common human malignancy. In this study, we aimed to investigate the serum levels of visfatin and miR-21 in HCC patients, to analysis the relationship between the pathological features and the plasma level of visfatin or miR-21, and to explore the roles of visfatin and miR-21 in migration of HCC cells. Our results showed that the serum levels of visfatin and miR-21 were significant higher in HCC patients than healthy subjects. The diagnostic sensitivity of serum visfatin was 82.5% and the specificity was 65.0%. The serum visfatin was significantly associated with the histology and metastasis. Visfatin induced miR-21 expression and cell migration in HepG2 cells. Transfection of miR-21 inhibitor suppressed the visfatin-induced migration in HCC cells. These results suggested that visfatin induced HCC cell migration via upregulation of miR-21, which provides a novel basis for the diagnosis of HCC.

The NCX1/TRPC6 Complex Mediates TGFβ-Driven Migration and Invasion of Human Hepatocellular Carcinoma Cells

TGFβ plays an important role in the progression and metastasis of hepatocellular carcinoma (HCC), yet the cellular and molecular mechanisms underlying this role are not completely understood. In this study, we investigated the roles of Na+/Ca2+ exchanger 1 (NCX1) and canonical transient receptor potential channel 6 (TRPC6) in regulating TGFβ in human HCC. In HepG2 and Huh7 cells, TGFβ-stimulated intracellular Ca2+ increases through NCX1 and TRPC6 and induced the formation of a TRPC6/NCX1 molecular complex. This complex-mediated Ca2+ signaling regulated the effect of TGFβ on the migration, invasion, and intrahepatic metastasis of human HCC cells in nude mice. TGFβ upregulated TRPC6 and NCX1 expression, and there was a positive feedback between TRPC6/NCX1 signaling and Smad signaling. Expression of both TRPC6 and NCX1 were markedly increased in native human HCC tissues, and their expression levels positively correlated with advancement of HCC in patients. These data reveal the role of the TRPC6/NCX1 molecular complex in HCC and in regulating TGFβ signaling, and they implicate TRPC6 and NCX1 as potential targets for therapy in HCC.Significance: TGFβ induces the formation and activation of a TRPC6/NCX1 molecular complex, which mediates the effects of TGFβ on the migration, invasion, and intrahepatic metastasis of HCC. Cancer Res; 78(10); 2564-76. ©2018 AACR.