Transcriptome Analysis of the Inhibitory Effect of Sennoside A on the Metastasis of Hepatocellular Carcinoma Cells

Sennoside A (SA) is a bioactive component of Rheum officinale Baill. with an activity of irritant laxative, which has been reported to possess therapeutic potential in various diseases or conditions including obesity, insulin resistance, liver steatosis, prostate cancer and pancreatic cancer progression. However, whether SA has therapeutic potential in hepatocellular carcinoma (HCC) treatment remains elusive. In this study, we treated two HCC cell lines, HepG2 and SMMC-7721 with SA and found that SA selectively inhibited the growth of HCC cells by proliferation assay. SA has a good inhibitory effect on proliferation of HepG2 cells in a concentration dependent manner, but there was no effect on SMMC-7721 cells. Then we conducted transwell assays and transcriptome analysis in HCC cells and examined the effects of SA on HCC in vivo. The results showed that SA significantly inhibited the migration and invasion of HCC. Comparison of RNA-seq transcriptome profiles from control groups and SA-treated groups identified 171 and 264 differentially expressed genes (DEGs) in HepG2 and SMMC-7721 cells respectively, in which includes 2 overlapping up-regulated DEGs and 12 overlapping down-regulated DEGs between HepG2 and SMMC-7721 cells. The qPCR were applied to investigate the transcriptional level of 9 overlapping down-regulated DEGs related to cancer metastasis, and the results were consistent with RNA-seq data. The dominate pathways including Wnt signaling pathway, TNF signaling pathway, VEGF signaling pathway, and NF-κB signaling pathway were strongly inhibited by SA, which are involved in regulating cancer metastasis. Finally, we confirmed that the downregulation of KRT7 and KRT81 could inhibit HCC metastasis. This study has provided new insight into the understanding of the inhibitory effects and potential targets of SA on the metastasis of HCC.

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Effect of PLC-β1/CaM signaling pathway mediated by AT1R on the occurrence and development of hepatocellular carcinoma

Cancer Cell International ◽

10.1186/s12935-021-02261-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zhou-wei Xu ◽

Na-na Liu ◽

Xing-yu Wang ◽

Bai-cheng Ding ◽

Hai-feng Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Liver Tissue ◽

Postoperative Survival ◽

Migration And Invasion ◽

Mouse Serum ◽

Ang Ii ◽

Expression Levels ◽

Target Proteins ◽

Hcc Cells

Abstract Objective To study the roles of AT1R, PLC-β1, CaM and other related signal molecules in the formation and development of hepatocellular carcinoma (HCC) and their correlation. Methods ELISA and immunohistochemistry were used to analyze the expressions of target proteins in serum and liver tissue of HCC patients, and the correlation between AT1R, PLC-β1 and CaM and postoperative survival status of patients was followed up and determined. CCK-8 method was used to screen the doses of Ang II and candesartan sensitive to HepG2 and HCCLM3 cells. Transwell experiment was used to observe the effects of different drugs on the migration and invasion activity of HCC cells. Meanwhile, flow cytometry and Western blot were used to detect the expression levels of AT1R, PLC-β1 and CaM in the cells. Then PLC-β1 siRNA was selected to transfect HCC cells, so as to further clarify the mechanism of the above signal proteins. HepG2 cells were inoculated under the hepatic capsule of mice to induce the formation of HCC in situ. Ang II and candesartan were used to stimulate HCC mice to observe the difference in liver appearance and measure the liver index. Finally, ELISA and immunofluorescence experiments were selected to analyze the levels of target proteins in mouse serum and liver tissue. Results The expression levels of target proteins in serum and liver tissue of HCC patients were significantly increased, and the postoperative survival time of patients with high expression of AT1R, PLC-β1 or CaM was obviously shortened. Ang II and candesartan could significantly promote and inhibit the motility of HCC cells, and had different effects on the levels of AT1R, PLC-β1 and CaM in cells. However, in hepatocellular carcinoma cells transfected with PLC-β1 siRNA, the intervention ability of drugs was obviously weakened. Ang II could significantly promote the formation and progression of mouse HCC, while candesartan had the opposite effect. Meanwhile, medications could affect the expressions of target proteins in mouse serum and liver tissue. Conclusion AT1R, PLC-β1 and CaM may be risk factors affecting the formation and prognosis of HCC, and the PLC-β1/CaM signaling pathway mediated by AT1R is an important way to regulate the migration and invasion activity of HCC cells.

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Vincosamide inhibits malignant behaviors of hepatocellular carcinoma cells by activating caspase-3 activity and blocking the PI3K/AKT signaling pathway

10.21203/rs.3.rs-28543/v1 ◽

2020 ◽

Author(s):

Mingyue Zhu ◽

Haipeng Feng ◽

Bo Lin ◽

Ying Zhou ◽

Yifeng Zheng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Caspase 3 ◽

Tumor Model ◽

Akt Signaling ◽

Migration And Invasion ◽

Mitochondrial Morphology ◽

Mouse Tumor ◽

Akt Signaling Pathway ◽

Hcc Cells

Abstract Background Vincosamide(Vinco) was first identified in the methanolic extract of the leaves of Psychotria leiocarpa, and Vinco has important anti-inflammatory effects and activity against cholinesterase. However, whether Vinco inhibits the malignant behaviors of hepatocellular carcinoma(HCC) cells is still unclear. In the present study, we explored the role of Vinco in suppressing the malignant behaviors of HCC cells. Methods MTT and trypan blue exclusion assays were applied to detect the proliferation and death of HCC cells; electron microscopy was performed to observe change in cellular mitochondrial morphology; scratch repair and Transwell assays were used to analyze the migration and invasion of HCC cells; the expression and localization of proteins were detected by laser confocal microscopy and Western blotting; and the growth of the cancer cells in vivo was assessed in a mouse tumor model. Results At a dose of 10–80 µg/ml, Vinco inhibited the proliferation of HCC cells and promoted their apoptosis in a time- and dose-independent manner but had little effect on normal liver cells. Additionally, 80 µg/ml Vinco significantly disrupted the morphology of mitochondria and suppressed the migration and invasion of HCC cells. The growth of HCC cells in the animal tumor model was significantly inhibited after treatment with Vinco (10 mg/kg/day) for 3 days. The results of the present study indicate that Vinco (10–80 µg/ml) plays novel roles in activating caspase-3, promoting the expression of PTEN, and inhibiting the phosphorylation of AKT(Ser 473) and mTOR (Thr2448) and that Vinco was able to also suppress the expression of CXCR4, Src, MMP9, EpCAM, Ras and Oct4 in HCC cells. Conclusions Vinco plays a role in inhibiting the malignant behaviors of HCC cells, and the molecular mechanism may involve in suppressing the expression of the growth-, metastasis-related factors Src, Ras, MMP9, EpCAM and CXCR4 and activating the activity of caspase-3. Vinco also blocks the PI3K/AKT signaling pathway. Thus, Vinco is an available chemotherapy for HCC patients.

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mascRNA and its parent lncRNA MALAT1 promote proliferation and metastasis of hepatocellular carcinoma cells by activating ERK/MAPK signaling pathway

Cell Death Discovery ◽

10.1038/s41420-021-00497-x ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Shu-Juan Xie ◽

Li-Ting Diao ◽

Nan Cai ◽

Li-Ting Zhang ◽

Sha Xiang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Mammalian Cells ◽

Mapk Signaling ◽

Mapk Signaling Pathway ◽

Migration And Invasion ◽

Clinical Samples ◽

Erk Mapk ◽

Lncrna Malat1 ◽

Hcc Cells

AbstractMALAT1-associated small cytoplasmic RNA (mascRNA) is a cytoplasmic tRNA-like small RNA derived from nucleus-located long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). While MALAT1 was extensively studied and was found to function in multiple cellular processes, including tumorigenesis and tumor progression, the role of mascRNA was largely unknown. Here we show that mascRNA is upregulated in multiple cancer cell lines and hepatocellular carcinoma (HCC) clinical samples. Using HCC cells as model, we found that mascRNA and its parent lncRNA MALAT1 can both promote cell proliferation, migration, and invasion in vitro. Correspondingly, both of them can enhance the tumor growth in mice subcutaneous tumor model and can promote metastasis by tail intravenous injection of HCC cells. Furthermore, we revealed that mascRNA and MALAT1 can both activate ERK/MAPK signaling pathway, which regulates metastasis-related genes and may contribute to the aggressive phenotype of HCC cells. Our results indicate a coordination in function and mechanism of mascRNA and MALAT1 during development and progress of HCC, and provide a paradigm for deciphering tRNA-like structures and their parent transcripts in mammalian cells.

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Total flavonoids of Radix Tetrastigma suppress inflammation-related hepatocellular carcinoma cell metastasis

Molecular Genetics and Genomics ◽

10.1007/s00438-020-01759-6 ◽

2021 ◽

Author(s):

Zhendong Liu ◽

Fangmi Ding ◽

Xingyong Shen

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Cell Migration ◽

Inhibitory Effect ◽

Migration And Invasion ◽

Total Flavonoids ◽

Cell Migration And Invasion ◽

Proinflammatory Mediators ◽

Cox 2 ◽

Hcc Cells

AbstractThis study aimed to investigate the effects of the total flavonoids of Radix Tetrastigma (RTF) on inflammation-related hepatocellular carcinoma (HCC) development. Extracted RTF was diluted to different concentrations for subsequent experiments. HCC cells were cotreated with lipopolysaccharide (LPS) and RTF to investigate the effects of RTF on LPS-stimulated HCC cells. A CCK-8 kit was used to measure cell proliferation. Apoptosis was detected with a flow cytometer. Cell migration and invasion were quantified by wound healing and Transwell assays, respectively. The expression of TLR4 and COX-2 and activation of the NF-κB pathway were determined by Western blotting. Treatment with LPS significantly enhanced cell proliferation and decreased the apoptosis rate, while cell migration and invasion were notably upregulated. RTF suppressed the proliferation and invasion induced by LPS stimulation and promoted HCC cell apoptosis. The protein levels of Bax and cleaved caspase-3 were decreased and that of Bcl-2 was increased by LPS in HCC cells, which could be rescued by RTF. RTF significantly inhibited the LPS-induced expression of the proinflammatory mediators IL-6 and IL-8 in HCC cells. Mechanistically, with RTF treatment, the upregulated expression of TLR4 and COX-2 induced by LPS was obviously downregulated. Furthermore, the phosphorylation of NF-κB/p65 was significantly decreased in LPS-stimulated cells after supplementation with RTF. Our study suggests that RTF exerts a significant inhibitory effect on the LPS-induced enhancement of the malignant behaviors of HCC cells via inactivation of TLR4/NF-κB signaling. RTF may be a promising chemotherapeutic agent to limit HCC development and inflammation-mediated metastasis.

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miR-186-5p Prevents Hepatocellular Carcinoma Progression Through Targeting METTL3 to Regulate m6A-Mediated Stabilization of FSTL5

10.21203/rs.3.rs-598803/v1 ◽

2021 ◽

Author(s):

DengYong Zhang ◽

FangFang Chen ◽

ShuoShuo Ma ◽

YongChun Zhou ◽

Wanliang Sun ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Rna Stability ◽

The Cancer Genome Atlas ◽

Cell Counting ◽

Migration And Invasion ◽

Dependent Manner ◽

Report Analysis ◽

Hcc Cells

Abstract Background: Hepatocellular carcinoma (HCC) processes in multi-steps which involves the sophisticated interactions of genetics, epigenetics, and transcriptional changes. According to before investigations, methyltransferase-like 3 (METTL3)-mediated m6A modification regulates the development of various cancers by regulating gene stability. However, the studies focusing on miRNA’s regulatory effect of N6-methyladenosine (m6A) modification on HCC progression are still limited. Methods: Immunochemistry (IHC) staining detected the histopathological changes in the tumor tissues. Cell Counting Kit-8 (CCK-8), clone formation, and transwell assay investigated the changes in cancer cell proliferation, invasion, and migration. The RNA m6A level was confirmed by methylated RNA immunoprecipitation. The RNA stability assay indicated the half-life (t1/2) of RNA in HCC cells. The prognosis of the indicated patients’ cohort was analyzed using the cancer genome atlas (TCGA) datasets. Luciferase report analysis was used to study the potential binding between microRNA (miRNA) and mRNA. A mice tumor transplant model was further established to study the changes in tumor progression. Results: Follistatin-like 5 (FSTL5) was found to be significantly downregulated in HCC, and it inhibited the further progression of HCC. The RNA stability analysis indicated that the mRNA t1/2 gene of HCC cells was shortened. Besides, METTL3 reduced the stability of FSTL5 mRNA in a m6A-YTH domain family 2(YTHDF2)-dependent manner. Functional experiments revealed that the downregulated METTL3 inhibited the HCC progression by up-regulating FSTL5 in vitro and in vivo. Luciferase report analysis confirmed that miR-186-5p directly targeted the METTL3. Additionally, miR-186-5p inhibited the proliferation, migration, and invasion of HCC cells by downregulating METTL3. We identified that miR-186-5p prevented the HCC progression by targeting METTL3 to regulate m6A-mediated FSTL5 stabilization. Conclusions: The miR-186-5p/METTL3/YTHDF2/FSTL5 axis perhaps point out a new direction for the targeted therapy of HCC.

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Vincosamide inhibits malignant behaviors of hepatocellular carcinoma cells by activating caspase-3 activity and blocking the PI3K/AKT signaling pathway

10.21203/rs.3.rs-86111/v1 ◽

2020 ◽

Author(s):

Mingyue Zhu ◽

Haipeng Feng ◽

Bo Lin ◽

Ying Zhou ◽

Yifeng Zheng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Caspase 3 ◽

Akt Signaling ◽

Cell Counting ◽

Migration And Invasion ◽

Mitochondrial Morphology ◽

Akt Signaling Pathway ◽

Related Factors ◽

Hcc Cells

Abstract Background: Vincosamide(Vinco) was first identified in the methanolic extract of the leaves of Psychotria leiocarpa, and Vinco has important anti-inflammatory effects and activity against cholinesterase, Vinco also has a trait to ant-tumor. However, whether Vinco is able to inhibit the malignant behaviors of hepatocellular carcinoma(HCC) cells is still unclear. In the present study, we explored the role of Vinco in suppressing the malignant behaviors of HCC cells.Methods: MTT, trypan blue exclusion assay and the Cell Counting Kit(CCK)-8 analysis were applied to detect the proliferation and death of HCC cells; electron microscopy was performed to observe the change of cellular mitochondrial morphology; scratch repair and Transwell assays were used to analyze the migration and invasion of HCC cells; the expression and localization of proteins were detected by laser confocal microscopy and Western blotting; and the growth of the cancer cells in in vivo was assessed in a mouse tumorous model.Results: At a dose of 10-80 mg/ml, Vinco inhibited the proliferation and promoted death of HCC cells in a dose-independent manner, but had low cytotoxcity effect on normal liver cells. Additionally, 80 mg/ml of Vinco could significantly disrupt the morphology of mitochondria, suppress the migration and invasion of HCC cells. The growth of HCC cells in the animal tumorous model was significantly inhibited after treatment with Vinco (10 mg/kg/day) for 3 days. The results of the present study indicated that Vinco (10-80 mg/ml) played a role in activating caspase-3, promoting the expression of PTEN, and inhibiting the phosphorylation of AKT(Ser473) and mTOR(Thr2448), Vinco also has a trait for suppressing the expression of CXCR4, Src, MMP9, EpCAM, Ras and Oct4 in HCC cells.Conclusions: Vinco has a role in inhibiting the malignant behaviors of HCC cells; the role molecular mechanism of Vinco maybe involve in restraining expression of the growth-, metastasis-related factors Src, Ras, MMP9, EpCAM and CXCR4, and activating the activity of caspase-3. Vinco also could block PI3K/AKT signaling pathway. Thus, Vinco is an available chemotherapy for HCC patients.

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CRISPR/Cas9-mediated knockout of NSD1 suppresses the hepatocellular carcinoma development via the NSD1/H3/Wnt10b signaling pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-019-1462-y ◽

2019 ◽

Vol 38 (1) ◽

Cited By ~ 3

Author(s):

Shuhua Zhang ◽

Fan Zhang ◽

Qing Chen ◽

Chidan Wan ◽

Jun Xiong ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Proliferation ◽

Signaling Pathway ◽

Malignant Tumor ◽

Quantitative Polymerase Chain Reaction ◽

Xenograft Model ◽

Migration And Invasion ◽

Mouse Xenograft Model ◽

Hcc Cells

Abstract Background The NSD family of histone lysine methyltransferases have emerged as important biomarkers that participate in a variety of malignancies. Recent evidence has indicated that somatic dysregulation of the nuclear receptor binding SET domain-containing protein 1 (NSD1) is associated with the tumorigenesis in HCC, suggesting that NSD1 may serve as a prognostic target for this malignant tumor. However, its mechanism in human hepatocellular carcinoma (HCC), the major primary malignant tumor in the human liver, remains unclear. Hence, we investigated how NSD1 regulated HCC progression via regulation of the Wnt/β-catenin signaling pathway. Methods Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis was performed to identify the expression of NSD1 in HCC cells and clinically obtained tissues. The relationship between NSD1 expression and prognosis was analyzed by Kaplan-Meier survival curve. Further, a NSD1 knockout cell line was constructed by CRISPR/Cas9 genomic editing system, which was investigated in a battery of assays such as HCC cell proliferation, migration and invasion, followed by the investigation into NSD1 regulation on histone H3, Wnt10b and Wnt/β-catenin signaling pathway via ChIP. Finally, a nude mouse xenograft model was conducted in order to assess tumorigenesis affected by NSD1 knockout in vivo. Results NSD1 was overexpressed in HCC tissues and cell lines in association with poor prognosis. Knockout of NSD1 inhibited the proliferation, migration and invasion abilities of HCC cells. CRISPR/Cas9-mediated knockout of NSD1 promoted methylation of H3K27me3 and reduced methylation of H3K36me2, which inhibited Wnt10b expression. The results thereby indicated an inactivation of the Wnt/β-catenin signaling pathway suppressed cell proliferation, migration and invasion in HCC. Moreover, these in vitro findings were reproduced in vivo on tumor xenograft in nude mice. Conclusion In conclusion, the study provides evidence that CRISPR/Cas9-mediated NSD1 knockout suppresses HCC cell proliferation and migration via the NSD1/H3/Wnt10b signaling pathway, suggesting that NSD1, H3 and Wnt10b may serve as potential targets for HCC.

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Artemisia argyi Essential Oil Inhibits Hepatocellular Carcinoma Metastasis via Suppression of DEPDC1 Dependent Wnt/β-Catenin Signaling Pathway

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.664791 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yanli Li ◽

Yang Tian ◽

Wei Zhong ◽

Ning Wang ◽

Yafeng Wang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Essential Oil ◽

Signaling Pathway ◽

Nude Mice ◽

Migration And Invasion ◽

Advanced Hepatocellular Carcinoma ◽

Dependent Manner ◽

Artemisia Argyi

The tumor metastasis is the major hurdle for the treatment of advanced hepatocellular carcinoma (HCC), due in part to the lack of effective systemic treatments. DEPDC1, a novel oncoantigen upregulated in HCC, is thought to be a molecular-target for novel therapeutic drugs. Artemisia argyi is a traditional Chinese medicine with anti-inflammatory and anti-tumor activities. This study investigated the potential therapeutic benefits of Artemisia argyi essential oil (AAEO) in suppressing metastasis of HCC by targeting DEPDC1. Assessment of AAEO cytotoxicity was performed by MTT assay. Anti-metastatic effects of AAEO were investigated in vitro using wound healing and transwell assays. The HepG2 cells were transduced with lentiviral vector containing luciferase (Luc). A metastasis model of nude mice was established by tail vein injection of HepG2-Luc cells. The nude mice were treated with AAEO (57.5, 115, and 230 mg/kg) or sorafenib (40 mg/kg). Metastasis of HCC cells was monitored via in vivo bioluminescence imaging. After treatment for 21 days, tissues were collected for histological examination and immunohistochemistry analysis. Gene and protein levels were determined by real-time quantitative PCR and western blotting. The results revealed that AAEO significantly inhibits the migration and invasion in vitro in a concentration-dependent manner. In vivo assays further confirmed that AAEO markedly inhibits HCC metastasis into lung, brain, and femur tissues and exhibits low toxicity. Our results suggested that AAEO significantly downregulates the mRNA and protein expression of DEPDC1. Also, AAEO attenuated Wnt/β-catenin signaling through reduction of Wnt1 and β-catenin production. Moreover, AAEO prevented epithelial-mesenchymal transition (EMT) by downregulation of vimentin and upregulation of E-cadherin. Furthermore, we found that DEPDC1 promoted HCC migration and invasion via Wnt/β-catenin signaling pathway and EMT. These results demonstrate that AAEO effectively inhibits HCC metastasis via attenuating Wnt/β-catenin signaling and inhibiting EMT by suppressing DEPDC1 expression. Thus, AAEO likely acts as a novel inhibitor of the DEPDC1 dependent Wnt/β-catenin signaling pathway.

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CircRNA hsa_circ_0110102 Function as Anti-Oncogenic Gene in Hepatocellular Carcinoma Through Modulating miR-580-5p/CCL2 Pathway

10.21203/rs.3.rs-62221/v1 ◽

2020 ◽

Author(s):

Xinxing Wang ◽

Wei Sheng ◽

Tao Xu ◽

Jiawen Xu ◽

Zhenhai Zhang

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Lines ◽

Molecular Mechanisms ◽

Luciferase Assay ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Dependent Manner ◽

Expression Levels ◽

Cox 2 ◽

Hcc Cells

Abstract Background: Circular RNAs (circRNAs) have been shown to have critical regulatory roles in tumor biology, whereas their contributions in hepatocellular carcinoma (HCC) still remains enigmatic. The purpose of this study was to investigate the molecular mechanisms involved in hsa_circ_0110102 in the occurrence and development of HCC. Methods: The expression levels of hsa_circ_0110102 in HCC cell lines and tissues were estimated by RT-qPCR assay. The proliferation, migration, and invasion of HCC cells were determined by CCK-8 and transwell assay. The western blot and ELISA were employed to examine the related-protein and cytokine expression. The association between miR-580-5p and hsa_circ_0110102 or CCL2 was predicted and affirmed by dual-luciferase reporter assay and RNA pull-down.Results: hsa_circ_0110102 was significantly down-regulated in HCC cell lines and tissues, low hsa_circ_0110102 expression levels were associated with poor prognosis. Knockdown hsa_circ_0110102 significantly inhibited cell proliferation, migration and invasion. In addition, luciferase assay and RNA pull-down assay indicating that hsa_circ_0110102 function as sponge for miR-580-5p. Moreover, miR-580-5p which could directly bind to the 3’-UTR of CCL2 and induce its expression, then active the COX-2/PGE2 pathway in macrophage via FoxO1 in p38 MAPK dependent manner. Furthermore, the Δ256 mutant of FoxO1 showed no activation effect. Conclusion: hsa_circ_0110102 act as a sponge for miR-580-5p and decreased CCL2 secretion in HCC cells, then inhibits pro-inflammatory cytokine release from activated macrophage by regulating the COX-2/PGE2 pathway. These results indicating that hsa_circ_0110102 serves as a potential prognostic predictor or therapeutic target for HCC.

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TDO2 Promotes the EMT of Hepatocellular Carcinoma Through Kyn-AhR Pathway

Frontiers in Oncology ◽

10.3389/fonc.2020.562823 ◽

2021 ◽

Vol 10 ◽

Author(s):

Lei Li ◽

Tao Wang ◽

Shanbao Li ◽

Zhengqian Chen ◽

Junyi Wu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Aryl Hydrocarbon Receptor ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Aryl Hydrocarbon ◽

Hcc Cells

Tryptophan 2,3-dioxygenase (TDO2), an enzyme involved in tryptophan (Trp) metabolism has been linked with some malignant traits of various cancers. Kyn, the main product of Trp metabolism pathway catalyzed by TDO2 and indoleamine 2,3-dioxygenase (IDO) in tumor cells, was also demonstrated to activate aryl hydrocarbon receptor (AhR), which may regulate cancer growth and invasion in some malignancies. However, whether TDO2 participates in the metastasis and invasion of HCC has not been explored before. The underlying mechanism played by TDO2 in this process still requires further investigation. Here, we demonstrated that overexpression of TDO2 correlates with advanced stage or malignant traits in HCC patients. Knockdown or inhibition of TDO2 suppressed the migration and invasion of HCC cells in vitro and in vivo. Epithelial to mesenchymal transition (EMT) is an essential program happened in the initial phase of cancer metastasis. We found that in HCC cells, TDO2 promoted the EMT process evidenced by altered levels of biomarkers for EMT. Mechanically, TDO2 regulated the Kyn production in HCC cell via activated aryl hydrocarbon receptor (AhR). Together, these results indicate that TDO2 promotes the EMT of hepatocellular carcinoma through activating Kyn-AhR pathway, thereby participating in the metastasis and invasion of HCC.

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