DEAH-box polypeptide 32 promotes hepatocellular carcinoma progression via activating the β-catenin pathway

doi:10.21203/rs.3.rs-27420/v1

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DEAH-box polypeptide 32 promotes hepatocellular carcinoma progression via activating the β-catenin pathway

https://doi.org/10.21203/rs.3.rs-27420/v1

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Background

Hepatocellular carcinoma (HCC) is a refractory cancer with high morbidity and high mortality. It has been reported that DEAH-box polypeptide 32 (DHX32) was upregulated in several types of malignancies and predicted poor prognosis, which was associated with tumor growth and metastasis. However, the expression of DHX32 in HCC and its role in HCC progression remain largely unknown.

Methods

Western blot and RT-PCR assays were used to detect the expression of DHX32 and epithelial mesenchymal transition (EMT)-related genes in HCC cells. Wound-healing and Transwell invasion assays were performed to determine the effect of DHX32 and β-catenin on the migration and invasion of HCC cells. Cell proliferation was examined by EdU cell proliferation assay.

Results

In our study, we found that high level of DHX32 expression was associated with reduced overall survival in HCC patients. DHX32 expression was upregulated in human HCC cells and ectopic expression of DHX32 induced EMT, promoted the migration, invasion, and proliferation of HCC cells, and enhanced tumor growth. Silencing DHX32 reversed EMT, inhibited the migration, invasion, and proliferation of HCC cells, and suppressed tumor growth. RT-PCR assay revealed that DHX32 regulated the expression of CTNNB1, CCND1, COX2, MMP7, and WIF1 in HCC cells. Mechanistic investigations showed that silencing DHX32 decreased the expression of β-catenin in nucleus and β-catenin siRNA abrogated DHX32-mediated EMT, migration, invasion, and proliferation in HCC cells.

Conclusions

Our data suggested that DHX32 was an attractive regulator of HCC progression and indicated DHX32 can serve as a potential biomarker and therapeutic target for HCC patients.

Cancer Biology

hepatocellular carcinoma

DHX32

EMT

proliferation

β-catenin

Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh in woman, which is the third leading cause of cancer deaths all around the world [1]. Surgical resection, trans-arterial chemoembolization and targeted therapy are the common treatments for early-stage HCC [2–4]. However, most HCC patients developed locally recurrence or metastasis after treatments, thus leading to limited benefits and poor outcomes [5, 6]. Therefore, further understanding of molecular mechanisms that contributed to HCC progression was important to identify a novel biomarker and therapeutic target for HCC patients.

Human RNA helicases, consisting of a number of the DEAH box proteins, are closely associated with RNA metabolism processes, such as splicing, degradation, transcription, and translation. They are highly conserved enzymes, and thus play an important role in gene expression [7, 8]. DEAH-box polypeptide 32 (DHX32, also known as DDX32) is a new member of the DEAH box helicase family and overexpressed DHX32 was observed in several kinds of solid tumors, including colorectal cancer [9, 10] and breast cancer [11, 12]. The expression of DHX32 was significantly related to clinically pathological features of colorectal cancer, and can be served as a prognostic biomarker for colorectal cancer patients [10]. It was reported that DHX32 overexpression promoted the proliferation and mobility of colorectal cancer cells and enhanced angiogenesis in colorectal cancer [9, 13]. Moreover, high level of DHX32 expression also predicted poor prognosis in breast cancer patients [11, 12]. However, the role of DHX32 in HCC progression remains largely unknown.

In our study, we aimed to explore the role of DHX32 in HCC progression. We found that high level of DHX32 expression negatively correlated with the overall survival in HCC patients and silencing DHX32 inhibited epithelial mesenchymal transition (EMT) and suppressed the migration, invasion, and proliferation of HCC cells. Mechanistically, DHX32-induced HCC progression was regulated by β-catenin pathway. These findings suggest a role of DHX32/β-catenin axis in HCC aggressiveness.

Cell culture

Human hepatocellular carcinoma cell lines HepG2, Hep3B, Huh7, SNU-182, and SNU-387 and human normal immortalized liver cell LO2 were purchased from ATCC. All cells were cultured in DMEM that was supplemented with 10% FBS and kept at 37℃ in a cell incubator with 5% CO₂.

Cell stable transfection

For DHX32 overexpression experiments, Huh7 cells were infected with DHX32 (NM_018180) Human Tagged ORF Clone Lentiviral Particle (Origene; Cat: RC209736L3V) or Lenti-ORF control particles of pLenti-C-Myc-DDK-P2A-Puro (Origene; Cat:PS100092V) using its recommending transfection reagent. For the knockdown of DHX32 experiments, Huh7 cells were infected with DHX32 human shRNA Lentiviral Particle (Santa Cruz Biotechnology; Cat: sc-77143-V) or control shRNA Lentiviral Particle. To establish stable cloning cells expressing or silencing DHX32, the infected cells were selected with 1 μg/ml Puromycin 2HCl (Selleck) for approximately 4 weeks. Then, the expression of DHX32 mRNA and protein was determined by RT-PCR and Western blot assays.

Cell transition transfection

For DHX32 and β-catenin co-transfection experiments, HCC cells were co-transfected with DHX32 lentiviral particle plus β-catenin siRNA I (SignalSilence; Cat: 6225). Control cells were co-transfected with corresponding vector and control siRNA. The transfection was performed with Lipofectamine™ 3000 Transfection Reagent (Invitrogen; Cat: L3000015) according to its protocol. The expression of DHX32 and β-catenin was detected by Western blot and TR-PCR assay.

Real-time polymerase chain reaction (RT-PCR) assay

Total RNA in HCC cells was extract with Total RNA Extraction Kit (Solarbio; Cat: R1200) according to its instruction. The concentration of mRNA was assessed using NanoDrop ND‐1000 spectrophotometer. Then, total RNA was mixed with All-in-One cDNA Synthesis SuperMix (Bimake; Cat: B24403) to generate cDNA. RT-PCR assay was performed with 2 × SYBR Green qPCR Master Mix (Bimake; Cat: B21202) in the LightCycler 480 Real-Time PCR System (Roche) in accordance with the manufactures’ protocol. The relative expression of targeted genes was calculated using 2^-ΔΔCt method and was normalized to the expression of ACTB in HCC cells.

Western blot analysis

Total protein in HCC cells was extracted with RIPA Lysis Buffer (Beyotime Technology; Cat: P0013C) containing protease inhibitors and phosphatase inhibitors. And nuclear protein was extracted with Nuclear and Cytoplasmic Protein Extraction Kit (Beyotime Biotechnology; Cat: P0027) according to its instruction. Then, the concentration of protein was assessed using a BCA Protein Kit (Invitrogen; Cat: 23227) and total protein was separated by Western blot assay. Bands were detected with Pierce™ ECL Western Blotting Substrate (Thermo Scientific; Cat: 32209). β-actin serves as a loading control.

EdU cell proliferation assay

EdU cell proliferation assay was conducted to examine the effect of DHX32 and β-catenin on HCC cell proliferation. Huh7 cells (3 × 10³) after different transfections were seeded in 96-well plates and maintained for 48 h. Then, cells were further incubated with 10 μM EdU reagent for 2 h and then performed according to the manufacture’s instruction (RiboBio; Cat: C10310-1). The number of EdU-stained cells were analyzed.

Cell migration assay

Wound-healing assay was used to detect the effect of DHX32 and β-catenin on HCC cell migration. Huh7 cells (2 × 10⁵) were seeded in 6-well plates and performed with transfection as indicated. When cells grew to nearly 90% confluency, cell monolayers were scratched with 200 μl pipette tips and followed by cell debris removal by PBS wash. Then, the wound width of cell monolayers was photographed at 36 h after scratch and the area of wound width was calculated with ImageJ software.

Cell invasion assay

Transwell invasion assay was performed to detect the effect of DHX32 and β-catenin on HCC cell invasion. Huh7 cells (4 × 10⁴) after the indicated transfections were suspended in serum-free medium were seeded into the Transwell inserts (Corning; Cat: 3422) that was pre-coated with diluted Matrigel (Corning; Cat: 356234). Then wells were filled with culture medium and incubated for 24 h. Next, cells were fixed and stained with 0.1% crystal violet. Invasive cells in the downside of the Transwell filters were observed and the number of invaded cells was calculated.

Tumor xenografts

Huh7 cells with DHX32 silencing or stable DHX32 overexpression were used to perform tumor xenograft assay. In brief, Huh7 cells (5 × 10⁶ cells/mL) were resuspended in diluted Matrigel (5 mg/mL) and subcutaneously injected into the flank of male Balb/c Nude mice (6 to 8 weeks old). After tumor engraftment, tumor sizes were measured every four days with calipers. Tumor volume was calculated using the formula: volume = π/6 × a × b² (a = longest diameter, b = shortest diameter perpendicular to a). Tumor weight was analyzed at 31 day after inoculation.

Statistical analysis

Data are shown as mean ± SEM. Statistical analysis were performed with GraphPad Prism 7.0 software and statistical differences were analyzed by unpaired two-tail Student’s t test or One-way analysis of variance (ANOVA) followed by post hoc test. P < 0.05 was considered statistically significant.

DHX32 is upregulated in HCC cells and predicts poor survival in HCC patients

The expression levels of DHX32 in human HCC cells and human immortalized normal liver LO2 cells were assessed by RT-PCR and Western blot assays. We found that the expression levels of DHX32 mRNA and protein were significantly higher in five HCC cell lines, including HepG2, Hep3B, Huh7, SNU-181, and SNU-387 cell, than those in human normal immortalized liver cell LO2 (Figure 1, A and B). In addition, we also found that high level of DHX32 expression had a negative correlation with overall survival in patients with HCC using Kaplan-Meier Plotter (Figure 1C). Together, these data indicate that DHX32 might serve as a contributor to HCC progression.

Ectopic expression of DHX32 induces EMT and enhances the migration, invasion, and proliferation of HCC cells

To explore whether ectopic expression of DHX32 promote HCC progression, the migration, invasion, and proliferation of HCC cells were tested. Huh7 cells after the indicated transfections were performed with RT-PCR assay, Western blot assay, wound-healing assay, Transwell invasion assay, and EdU cell proliferation assay. We confirmed that the expression levels of DHX32 mRNA and protein were upregulated in Huh7 cells transfected with DHX32 lentiviral particles compared with cells transfected with vector lentiviral particles (Figure 2, A and B). Epithelial mesenchymal transition is one of the key regulators of invasion and metastasis in HCC [14]. We found that the overexpression of DHX32 induced EMT in HCC cells, leading to the upregulation in the expression of mesenchymal markers N-cadherin and vimentin and the reduction in the expression of epithelial marker E-cadherin (Figure 2, B and C). Then, the effect of DHX32 on HCC cell migration and invasion was examined. Wound-healing assay revealed that DHX32 overexpression increased the migration capacity of Huh7 cells and facilitated the closure of wound width of cell monolayers (Figure 2D). We also observed that the overexpression of DHX32 significantly increased the number of invasive HCC cells (Figure 2E). Moreover, we also detected the effect of DHX32 on HCC cell proliferation. EdU cell proliferation assay showed that ectopic expression of DHX32 promoted HCC cell proliferation, as evidenced by much increase in the number of EdU-positive Huh7 cells (Figure 2F). Taken together, our results suggest that the overexpression of DHX32 induces EMT and promotes the mobility and growth of HCC cells.

The knockdown of DHX32 reverses EMT and inhibits the migration, invasion, and proliferation of HCC cells

Next, we further investigated the effect of DHX32 knockdown on HCC progression. The expression of DHX32 in Huh7 cells were stably silenced with its specific shRNA lentiviral particles. RT-PCR and Western blot assays showed that the expression of DHX32 was dramatically downregulated in Huh7 cells infected with DHX32 shRNA lentiviral particles (Figure 3, A and B). Then, whether inhibition of DHX32 suppressed EMT in HCC cells was determined. We found that DHX32 shRNA dramatically increased E-cadherin mRNA and protein expression levels, while decreased the expression of N-cadherin and vimentin in Huh7 cells, which indicated that DHX32 shRNA inhibited EMT (Figure 3, B and C). Wound-healing assay showed that silencing DHX32 inhibited the closure of wound width of Huh7 cell monolayers (Figure 3D). Transwell invasion assay revealed that the knockdown of DHX32 remarkably reduced the invasive capacity of HCC cells (Figure 3E). In addition, we found that DHX32 shRNA significantly decreased the number of EdU-positive Huh7 cells compared with cells transfected with control shRNA (Figure 3F). Thus, these data suggest that silencing DHX32 suppresses EMT and inhibits the migration, invasion, and proliferation of HCC cells.

DHX32 regulates the activation of β-catenin pathway in HCC cells

We next investigated the mechanisms of DHX32-medaited EMT and aggressiveness in HCC cells. Since various signaling pathways are involved in EMT and tumor progression, we traced β-catenin pathway. We found that the overexpression of DHX32 increased CTNNB1 mRNA expression in Huh7 cells (Figure 4A). Then, we performed Western blot assay to determine whether DHX32 increased the expression β-catenin in nucleus, which is responsible for the activation of β-catenin pathway. We found that the expression of β-catenin in nucleus was much higher in Huh7 cells after transfection with DHX32 lentiviral particle than vector (Figure 4B). RT-PCR assay revealed that ectopic expression of DHX32 upregulated the mRNA expression of CCND1, COX2, and MMP7 that were the target genes of β-catenin pathway (Figure 4C). DHX32 overexpression also reduced the expression of WIF1, a negative regulator of Wnt/β-catenin pathway (Figure 4C). Moreover, we further determined whether DHX32 knockdown inactivated β-catenin pathway in Huh7 cells. We found that silencing DHX32 downregulated the expression of CTNNB1 mRNA and decreased the expression of β-catenin in nucleus of Huh7 cells (Figure 4, D and E). In addition, RT-PCR assay further confirmed that the knockdown of DHX32 downregulated the mRNA expression of CCND1, COX2, and MMP7, while upregulated the expression of WIF1 mRNA in HCC cells (Figure 4F). Together, these findings suggest that DHX32 could activate β-catenin pathway in HCC cells via promoting the expression of β-catenin in nucleus.

β-catenin siRNA abrogates DHX32-induced EMT, migration, invasion, and proliferation in HCC cells

Then, we further determined the role of β-catenin in DHX32-mediated mobility and growth in HCC cells. Huh7 cells with stably overexpression of DHX32 were transfected with β-catenin siRNA or control siRNA. RT-PCR and Western blot assays revealed that DHX32 lentiviral particle significantly upregulated the mRNA and protein expression of β-catenin in Huh7 cells, which was downregulated in cells after co-transfection with DHX32 lentiviral particle plus β-catenin siRNA (Figure 5, A and B). Then, we detected whether DHX32-induced EMT in HCC cells can be reversed by β-catenin siRNA. We found that β-catenin siRNA reversed DHX32-induced EMT in HCC cells, and led to the increase in E-cadherin expression and the downregulation of N-cadherin and vimentin expression (Figure 5, C and D). Expectedly, we found that β-catenin siRNA decreased the ability of DHX32 to increase the proliferation of Huh7 cells and resulted in a significant decrease in the number of EdU-positive cells (Figure 5E). Wound-healing assay revealed that the closure of wound width was attenuated in cells after co-transfection with DHX32 lentiviral particle plus β-catenin siRNA, when compared to cells after transfection with DHX32 lentiviral particle (Figure 5F). In addition, we also found that β-catenin siRNA reduced the activity of DHX32 to promote the invasion capacity of HCC cells and decreased the number of invasive cells (Figure 5G). Taken together, these results demonstrate that DHX32-mediated HCC progression is regulated by β-catenin pathway.

Inhibition of DHX32 suppresses HCC tumor growth

Next, we tested the effect of DHX32 on HCC tumor growth. Huh7 cells after the indicated transfections were subcutaneously injected into the flank of male Balb/c Nude mice and tumor sizes were measured every five day for 4 weeks. Compared to Huh7 cells transfected with control shRNA, silencing DHX32 impaired tumor growth (Figure 6A) and decreased the weight of Huh7 xenograft tumors (Figure 6B). Furthermore, we found that ectopic expression of DHX32 promoted HCC tumor growth in comparison with vector-transfected groups (Figure 6, C and D). Therefore, our in vivo study indicates that suppression of DHX32 blocks HCC tumor growth.

The correlation between DHX32 and cancer progression has been explored in several kinds of cancers. DHX32 was reported to function as either a cancer-promoting or a tumor-suppressive gene depending on tumor types, which indicated that the regulation of DHX32 in tumor development might be complex. The expression of DHX32 was upregulated in colorectal cancer (CRC) tissues and remarkably related to local or lymphatic metastasis, differentiation grade, and Dukes’ stage in CRC patients [10]. DHX32 also overexpressed on human CRC cell lines, such as SW480, SW620, and LS174T cells, which enhanced their proliferation and mobility capacities and decreased the chemosensitivity to 5-Fluorouacil [9]. Moreover, DHX32 expression was demonstrated to be negatively correlated with overall survival and disease-free survival in breast cancer patients and could serve as a potential therapeutic target [11]. However, DHX32 was downregulated in acute lymphoblastic leukemia and might regulate lymphopoiesis [15]. In our study, we found that downregulated expression of DHX32 had a positive correlation with overall survival in patients with HCC. The expression of DHX32 was increased in HCC cell lines than LO2 cells. We also found that the proliferation, migration and invasion of HCC cells were enhanced by ectopic expression of DHX32, which was reduced by DHX32 silencing. Our study indicated a important role of DHX32 in HCC progression.

Aberrant activation of the canonical Wnt/β-catenin pathway was observed in multiple types of cancer, including HCC [16–18]. Currently, accumulating studies have reported that β-catenin pathway is closely implicated in the growth, EMT, and metastasis of many kinds of solid tumors, such as glioma [19], prostate cancer [20], colorectal cancer [21], and HCC [22]. And inhibiting β-catenin is proven to be a promising therapeutic target for cancers [23–25]. In addition to Wnt ligand-dependent activation, the activation of β-catenin pathway can be trigger in a ligand-independent manner. For example, prospero-related homeobox 1 (PROX1) can enhance the proliferation and decrease the sensitivity to sorafenib in HCC cells through activating the β-catenin pathway [26]. Moreover, Src-homology 2 domain-containing phosphatase 2 (SHP2) promoted the dedifferentiation and enhanced the self-renewal of liver cancer stem cells by augmenting the β-catenin pathway [27]. In our study, we found that the knockdown of DHX32 inhibited the activation of β-catenin and downregulated the target genes of β-catenin pathway. These results indicated that DHX32 might be an upstream regulator of the β-catenin pathway. In addition, β-catenin siRNA can impair DHX32-induced HCC progression. These findings further confirmed that DHX32 promoted the proliferation, migration and invasion via amplifying β-catenin pathway.

Many biological processes are involved in β-catenin signaling activation, such as decreasing β-catenin degradation and promoting the expression and nuclear translocation of β-catenin [28–30]. PROX1 promoted HCC progression via enhancing the expression and nuclear translocation of β-catenin [26]. SHP2 facilitated the nuclear translocation of β-catenin by dephosphorylation of CDC73 and phosphorylation of GSK-3β [27]. In our study, we found that DHX32 siRNA downregulated the mRNA expression of β-catenin and decreased the expression of β-catenin in nucleus of HCC cells. However, the underlying molecular mechanisms of DHX32 in augmenting β-catenin signaling remained to be further investigated. In addition, intrahepatic metastasis and distant metastasis are the leading causes of poor clinical outcomes in HCC patients [6]. In our in vivo study, we observed that inhibition of DHX32 suppressed HCC tumor growth. In vitro studies revealed that the knockdown of DHX32 blocked the migration and invasion of HCC cells. Thus, more research is needed to evaluate the effect of DHX32 on HCC metastasis in orthotopic HCC models.

In conclusion, the experimental study reported that overexpressed DHX32 was significantly associated with EMT and increased migration, invasion, and proliferation capacities in HCC cells. Further mechanistic investigations revealed that β-catenin pathway was responsible for DHX32-mediated HCC progression. Our findings demonstrated that targeting DHX32 might be a promising therapeutic strategy for HCC patients.

Hepatocellular carcinoma: HCC; DEAH-box polypeptide 32: DHX32; Epithelial mesenchymal transition: EMT; Real-time polymerase chain reaction: RT-PCR; Colorectal cancer: CRC; Prospero-related homeobox 1: PROX1; Src-homology 2 domain-containing phosphatase 2: SHP2.

Ethics approval and consent to participate

All animal studies were performed under the protocols approved by the Ethics Committee of Nanfang Hospital, Southern Medical University.

Consent for publication

All authors have read the manuscript and given consent for publication.

Availability of data and materials

All data and materials relevant to this study are available in the article.

Competing interests

None declared.

Funding

The study was supported by Nanfang Hospital of Southern Medical University.

Authors' contributions

JZ Chen conceived and designed this study. XY Hu drafted and wrote the manuscript. XY Hu, GS Yuan, and Q L performed the in vitro experiments. GS Yuan, J Huang, and X Cheng performed the animal studies.

Acknowledgements

Not applicable.

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Journal Publication

published 01 Jan, 2021

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DEAH-box polypeptide 32 promotes hepatocellular carcinoma progression via activating the β-catenin pathway

Status:

Journal Publication

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Abstract

Background

Methods

Results

Conclusions

Figures

Background

Materials And Methods

Results

Discussion

Conclusions

Abbreviations

Declarations

References

Status:

Journal Publication

Version 1