Overexpression of CTNND1 in hepatocellular carcinoma promotes carcinous characters through activation of Wnt/β-catenin signaling
© Tang et al. 2016
Received: 8 February 2016
Accepted: 10 April 2016
Published: 18 May 2016
Increasing evidence supports the association of CTNND1 with tumor development and progression. However, the mechanism and clinical significance of CTNND1 deregulation in hepatocellular carcinoma (HCC) remains unknown. In this study, we aim to investigate the role of CTNND1 in HCC.
qRT-PCR and immunohistochemical analyses were used to measure the levels of CTNND1 in HCC specimens and HCC cell lines. CTNND1 and shCTNND1 were transfected into HCC cell lines to investigate its role in HCC. Cell migration and invasion were measured by Transwell and Matrigel analyses in vitro. In vivo metastasis assays were performed in SCID mice.
In clinical HCC samples, we found that CTNND1 expression was significantly up-regulated in cancer lesions compared with paired normal liver tissues. By silencing or overexpressing CTNND1 in HCC cells, we found that CTNND1 could promote cell proliferation, migration, and invasion in vitro. An in-vivo assay showed that CTNND1 dramatically promoted HCC cell tumor formation and metastasis. Moreover, CTNND1 promoted HCC metastasis, at least in part, by indirectly enhancing Wnt/β-catenin signaling. Consistent with these results, the expression of CTNND1 was positively correlated with β-catenin, WNT11, Cyclin D1, and BMP7 expression in human HCC specimens.
Our study provides evidence that CTNND1 functions as a novel tumor oncogene in HCC, and may be a potential therapeutic target for HCC management.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide [1–3]. The vast majority of HCCs arise in the context of chronic liver injury, inflammation, and hepatocyte proliferation provoked by different etiologies [4, 5]. HCCs have a highly variable clinical course, and include several subgroups with distinct pathways of hepatocarcinogenesis . These processes share common mechanisms with embryogenesis and can be considered as an aberrant form of organogenesis [7, 8]. Surgical resection and liver transplantation are available options for the treatment of early-stage HCC; however, the prognosis of HCC remains poor because of a high level of tumor invasiveness, frequent intrahepatic spread, extrahepatic metastasis, and resistance to chemotherapy.
Cell - cell contact is initiated and maintained by the adherens junction (AJ). AJs are complexes that are located at the basolateral membrane, and are composed of classical cadherins . The cadherin cytoplasmic domain directly interacts with CTNND1 (δ-catenin) and β-catenin (CTNNB1). Together with α-catenin (CTNNA1), which binds to β-catenin and links the AJ to the actin cytoskeleton, they form the core AJ complex . Accumulating evidence has revealed that the Armadillo catenins are multifunctional nucleo-cytoplasmic shuttling proteins that regulate gene expression via interaction with DNA-binding transcriptional factors . This activity is best illustrated by β-catenin, which is translocated into the nucleus, where it functions as a co-transcriptional factor in Wnt/β-catenin signaling. In contrast to β-catenin, the role of CTNND1 has been less elucidated. CTNND1 first attracted attention when the known transcriptional factor Kaiso was identified as a CTNND1-specific binding partner . Kaiso inhibits β-catenin/TCF activation of target genes, and CTNND1 inhibits Kaiso activity. Thus, it is now thought that the Kaiso/CTNND1 complex is a modulator of the canonical Wnt/β-catenin signaling pathway . Recently, a large amount of data has implicated CTNND1 in the regulation of cancer development and progression [12–14]. CTNND1 can function as an oncogene that drives migration and anchorage independence, both of which are established hallmarks of metastatic cancer [15, 16]. These results suggest that CTNND1 plays a role in the oncogenesis of some malignancies. However, whether CTNND1 expression contributes to HCC development and progression is not known.
In the present study, we sought to determine whether and, if so, how CTNND1 regulates the growth and invasion of HCC cells. We found that CTNND1 expression was significantly up-regulated in cancer lesions compared with paired normal liver tissues. By silencing or overexpressing CTNND1 in HCC cells, we found that CTNND1 could promote cell proliferation, migration, and invasion in vitro. An in-vivo assay showed that CTNND1 dramatically promoted HCC cell tumor formation and metastasis. Moreover, CTNND1 promoted HCC metastasis, at least in part, by indirectly interacting with Wnt/β-catenin to enhance Wnt/β-catenin signaling. Consistent with these results, the expression of CTNND1 was positively correlated with β-catenin, WNT11, Cyclin D1, and MMP7 expression in human HCC specimens. Our study provides evidence that CTNND1 functions as a novel tumor oncogene in HCC, and may be a potential therapeutic target for HCC management.
Chemicals and antibodies
Lipofectamine 2000 transfection and Trizol LS reagents were purchased from Invitrogen (Grand Island, NY, USA). Antibodies against CTNND1, WNT11, β-catenin, Cyclin D1, MMP7, and Kaiso were purchased from Abcam (Cambridge, MA, USA). E-cadherin, N-cadherin, vimentin, and β-actin antibodies were from Cell Signaling Technology (Danvers, MA, USA). Anti-α-catenin antibody was from BD (Franklin Lakes, NJ, USA).
Patients and specimens
CTNND1 staining and clinicopathologic characteristics of 289 hepatocellular carcinoma patients
89 (77 %)
27 (23 %)
131 (76 %)
42 (24 %)
163 (69 %)
27 (31 %)
42 (78 %)
12 (22 %)
53 (65 %)
28 (35 %)
151 (73 %)
57 (27 %)
185 (76 %)
57 (24 %)
31 (66 %)
16 (34 %)
64 (69 %)
27 (31 %)
136 (68 %)
60 (32 %)
113 (81 %)
26 (19 %)
110 (73 %)
40 (27 %)
41 (66 %)
22 (34 %)
159 (70 %)
68 (30 %)
Tumor diameter (cm)
178 (70 %)
77 (30 %)
15 (44 %)
19 (56 %)
92 (80 %)
23 (20 %)
63 (36 %)
111 (64 %)
83 (62 %)
50 (38 %)
91 (58 %)
65 (42 %)
I + II
135 (71 %)
56 (29 %)
III + IV
31 (32 %)
67 (68 %)
161 (69 %)
73 (31 %)
II + III
32 (58 %)
23 (42 %)
Histological and immunohistochemical analysis
The normal human liver tissues, human tumor tissues, and lungs dissected from mice were fixed in 4 % paraformaldehyde in phosphate-buffered saline (PBS) overnight and subsequently embedded in paraffin wax. Sections cut at a thickness of 4 μm were stained with hematoxylin and eosin for histological analysis. Immunohistochemical analysis was performed for different markers in these arrays as described previously. The proportion of stained cells (low, <30 % staining; high, ≥30 % staining) was semiquantitatively determined following published protocols [17, 18].
HCC cells (ATCC, Manassas, VA, USA) were cultured under the following conditions: SNU-449, HCCLM3, HepG2, SK-Hep-1, and MHCC97H cell lines were cultured using 10 % fetal bovine serum (Invitrogen) in RPMI-1640 (Invitrogen). The HL7702 cell line was cultured using 10 % fetal bovine serum in Dulbecco's modified Eagle medium (Invitrogen). Cell culture was according to the manufacturer’s protocol. All the cell lines were grown at 37 °C in a 5 % CO2/95 % air atmosphere, and were revived every 3 to 4 months.
Establishment of CTNND1 stable expression and knockdown cell lines
Retroviral constructs containing human pBabe-CTNND1 cDNA and pSuper.retro.puro with shRNA against human CTNND1 were prepared as described previously [17, 19]. The generation of retrovirus supernatants and transfection of hepatocellular carcinoma cells were conducted as described previously [17, 20]. The expression of CTNND1 was confirmed by qRT-PCR and Western blotting analysis.
The transfected cells were seeded in 96-well plates at a density of 3× 103 cells/well. MTT solution (20 μ of 5 mg/ml MTT) was added to each well (for a total volume of 250 μl), and the plates were incubated for 4 h at 37 °C. Following the removal of the culture medium, the remaining crystals were dissolved in DMSO, and the absorbance was measured at 570 nm using a microplate reader. Cell proliferation was assessed daily for four consecutive days.
Cells were seeded in 6-cm culture plates. Cell monolayers were wounded by scratching with sterile plastic 200-μl micropipette tips, and were photographed using phase-contrast microscopy. The migration distance of each cell was measured after the photographs were converted to Photoshop files.
Cell invasion and motility assays
Invasion of cells was measured in Matrigel-coated (BD, Franklin Lakes, NJ, USA) Transwell inserts (6.5 mm, Costar, Manassas, VA, USA) containing polycarbonate filters with 8-μm pores as detailed previously [21, 22]. The inserts were coated with 50 μl of 1 mg/ml Matrigel matrix according to the manufacturer’s recommendations. Cells (2 × 105) in 200 μl of serum-free medium were plated in the upper chamber, and 600 μl of medium with 10% fetal bovine serum was added to lower well. After a 24-h incubation, cells that had migrated to the lower surface of the membrane were fixed and stained. For each membrane, five random fields were counted at × 10 magnification. Motility assays were similar to Matrigel invasion assays except that the Transwell insert was not coated with Matrigel.
Cells were lysed in lysis buffer and total protein contents were determined by the Bradford method. Proteins (30 μg) were separated by reducing SDS-PAGE, and probed with specific antibodies. Blots were washed and probed with respective secondary peroxidase-conjugated antibodies, and the bands were visualized by chemoluminescence (Amersham Biosciences, Shanghai, China).
Confocal immunofluorescence microscopy
Cell lines were plated onto culture slides (Costar, Manassas, VA, USA). After 24 h, the cells were rinsed with PBS and fixed with 4 % paraformaldehyde in PBS. Cell membranes were permeabilized using 0.5 % Triton X-100. The cells were then blocked for 30 min in 10 % BSA in PBS, and then incubated with primary antibodies in 10 % BSA overnight at 4 °C. After three washes in PBS, the slides were incubated for 1 h in the dark with FITC-conjugated secondary goat anti-mouse, or goat anti-rabbit antibodies (Invitrogen). After three further washes, the slides were stained with DAPI for 5 min to visualize the nuclei, and were examined using a Carl Zeiss confocal imaging system (LSM 780; Carl Zeiss, Jena, Germany).
Total RNA was extracted using Trizol reagent, and cDNA was synthesized using SuperScript-Reverse Transcriptase (Invitrogen). qRT-PCR and data collection were performed with an ABI PRISM 7900HT sequence detection system. The primers used for the amplification of the indicated genes are available upon request.
Gene expression profiling
Total RNA quality and quantity were determined using an Agilent 2100 Bioanalyzer and NanoDrop ND-1000. Affymetrix HU U133 plus 2.0 arrays were used according to the manufacturer’s protocol. The data were initially normalized by robust multiarray average (RMA) normalization algorithms in the expression console software (Affymetrix). Significantly altered genes between CTNND1-overexpressing cells and the control cells were considered by scatter plots and the genes up- and down-regulated by ≥5-fold. Clustering analysis was done using a gene list by Gene Cluster v3.0 software, and heat maps were visualized using Java TreeView v1.1.4r3 software. Gene-set enrichment analysis was carried out using ConceptGen. Gene sets were either obtained from ConceptGen or from published gene signatures.
In-vivo tumor growth and metastasis
Nude mice were purchased from the Shanghai Slac Laboratory Animal Co. Ltd., and were maintained in microisolator cages. All animals were used in accordance with institutional guidelines, and the current experiments were approved by the Use Committee for Animal Care. For subcutaneous inoculation, different numbers of tumor cells were resuspended in PBS medium with 50 % Matrigel, and were inoculated subcutaneously into the 8-week-old nude mice. The tumors were measured weekly, and the tumor volume was calculated according to the formula: length × width2/2. The mice were killed 40 days after the inoculation. For metastasis assays, cells were resuspended in PBS at a concentration of 1x107 cells ml-1. Cell suspension (0.1 ml; 1x106 cells) was injected into tail veins of nude mice. All of the mice were killed by CO2 60 days after inoculation.
Results were analyzed with SPSS13.0 statistical software. Correlation between CTNND1 expression and clinicopathologic parameters was evaluated using the Chi-square (χ2) test, and quantitative variables were analyzed by the independent t test. The survival probability was estimated by the Kaplan–Meier method, and the comparison of survival curves between groups was done with the log-rank test. The statistical significance of the differences between mean values was determined by P <0.05.
CTNND1 is highly expressed and correlated with distant metastasis in HCCs
CTNND1 promotes the proliferative capacity of HCC cells both in vitro and in vivo
Compared to vector-only controls, silencing of CTNND1 in SK-Hep-1 cells significantly reduced cell proliferation by the MTT assay (Fig. 3e), In contrast, overexpression of CTNND1 in SNU-449 cells significantly increased cell proliferation (Fig. 3f). To extend our in-vitro observations, we investigated whether CTNND1 could regulate tumorigenic capacity of HCC cells in vivo. SK-Hep-1-shCTNND1 #1 and SNU-449-CTNND1 cells, and their corresponding control cells, were subcutaneously injected into nude mice. As expected, silencing of CTNND1 in the typically aggressive SK-Hep-1 cells led to a dramatic decrease in tumor volume and weight (Fig. 3g and h). In contrast, SNU-449-CTNND1 cells grew more rapidly at the implantation site than the control cells (Fig. 3i and j). Taken together, these results suggest that CTNND1 is an important regulator of proliferation in HCC cells.
CTNND1 promotes migratory and invasive capacities of HCC cells in vitro and metastasis in vivo
CTNND1 regulates the transition between epithelial and mesenchymal phenotypes in HCC cells
CTNND1 enhances Wnt/β-catenin signaling in HCC cells
These data also led us to hypothesize that CTNND1 exerts these functions via regulation of Wnt/β-catenin signaling. To test this, we first determined whether β-catenin is a downstream target of CTNND1 in HCC cells. Expression of β-catenin in the cells with altered CTNND1 expression was evaluated by qRT-PCR and Western blotting. Silencing CTNND1 in SK-Hep-1 cells dramatically decreased β-catenin mRNA and protein levels (Fig. 7c and d), whereas SNU-449-CTNND1 cells exhibited greatly increased β-catenin protein and mRNA levels (Fig. 7e and f).
Wnt/β-catenin signaling is a mediator for CTNND1-induced proliferative migration, and invasion in HCC cells
In this research, we delineated for the first time the clinical significance of CTNND1 in HCC and the mechanistic role of CTNND1 in regulating HCC cell proliferation and metastasis. To our knowledge, this is the first study to show that CTNND1 plays a functional role in HCC cell proliferation, migration, invasion, and metastasis. CTNND1 overexpression in HCC cells induced EMT, migration, and invasion traits in vitro and enhanced metastatic capacity in vivo. In contrast, silencing CTNND1 reversed these events in otherwise aggressive and invasive HCC cells. We also showed that a mechanistic link exists between CTNND1 and Wnt/β-catenin signaling through direct interaction with the transcriptional repressor Kaiso, which subsequently leads to transcriptional upregulation of Wnt/β-catenin signaling expression. These results lead us to propose a model for CTNND1 regulation of EMT, migration, invasion, and metastasis through regulation of Wnt/β-catenin signaling in HCC cells.
The putative role of CTNND1 as an oncogene in cancer development is supported by the observations that CTNND1 is highly expressed in some tumors relative to normal tissues . It is well recognized that inactivation of E-cadherin leads to cytosolic translocation of CTNND1 in colon, breast, bladder, lung, pancreas, prostate, and stomach tumors, which has been associated with tumor malignancy . Indeed, studies in breast and colon cancer indicate that cytosolic CTNND1 controls the invasive phenotype of E-cadherin-deficient tumor cells . Furthermore, a switch from E-cadherin expression to P-cadherin, which is associated with a more invasive behavior, in ovarian and pancreatic cancer cell lines results in the translocation of CTNND1 to the cytosol, which in turn induces cell migration by activating RAC1 and CDC42 . Our study points to a novel function of CTNND1 in HCC metastasis through promoting two essential characteristics of metastatic disease in HCCs: migration and invasion [27, 28]. First, HCC cells expressing high levels of CTNND1 displayed an EMT phenotype, including the associated stimulatory effects on in-vitro migration and invasion. Interestingly, our results indicate that CTNND1 not only promotes EMT, but silencing of CTNND1 also leads to MET. Thus, CTNND1 promotes characteristics of migration that have been proposed as a model for cancer progression and metastasis. All of these characteristics that are induced by CTNND1 in vitro culminated in increased numbers of distant metastases in vivo. These empirical findings provide a mechanistic framework to explain the clinical observations that HCC patients with high levels of CTNND1 in tissue samples have more chance of distant metastasis, and a significantly shorter overall and disease-free survival.
The roles of several transcription factors as EMT regulators have been extensively reported [29–31]. In our effort to elucidate the mechanism by which CTNND1 modulates metastasis traits in HCC cells, we identified the Wnt/β-catenin signaling as an effective mediator of CTNND1-induced phenomena. It has been implicated that oxidative stress in the tumor microenvironment enhances canonical Wnt/beta-catenin signaling cascade, which is involved in the collective cell migration of the several kinds of solid tumors . In this study, we found that modulation of CTNND1 expression altered the Wnt/β-catenin signaling. Previous studies have shown that CTNND1 can modulate gene expression through its direct interaction with the transcriptional repressor Kaiso . Kaiso is a member of the BTB family of transcription factors that can bind to methylated DNA and/or a specific Kaiso binding sequence. Binding of CTNND1 to Kaiso might inhibit its DNA binding and relieve the repression of its target genes, such as WNT11, CyclinD1, and MMP7, which have been linked to non-canonical and canonical WNT-dependent developmental processes . In accordance with previous studies, in the present study, we also found that ectopic CTNND1 remarkably increased the level of β-catenin, WNT11, Cyclin D1, and MMP7 at both the protein and mRNA level, whereas silencing CTNND1 robustly suppressed β-catenin, Wnt11, Cyclin D1, and MMP7 expression in HCC cells. Previous study has found that activation of canonical Wnt/β-catenin signaling enhances in vitro motility of cancer cells by activation of ZEB1 and other activators of epithelial-to-mesenchymal transition . Thus, the CTNND1 induced activation of Wnt/β-catenin signaling promotes HCC cells ETM formation may partly by ZEB1.
Migration, invasion, and metastasis properties are essential for HCC cells to disseminate from adjacent tissues and to seed new tumors in distant sites. Our results demonstrate that CTNND1 regulated these essential characteristics of metastatic disease, and that CTNND1-induced processes are reversible with the suppression of CTNND1 expression, thus providing us with a potential therapeutic option to manipulate CTNND1 levels in clinical HCC practice.
We wish to particularly acknowledge the patients enrolled in this study for their participation, and the Department of Pathology and Physiopathology, Guilin Medical University, for its collaboration in providing the human samples and the clinical information used in this project with appropriate ethics approval.
This research was supported in part by The National Natural Science Foundation of China (No.81060094, No. 81360367, No. 81160066, and No. 30870719); Scientific Research Foundation for Returned Scholars, Ministry of Education of China (jyb2010-01); Major Project of Science Research of Guangxi Universities (2013ZD046); The Natural Science Foundation of Guangxi (2014GXNSFBA118162), Special Project of Traditional Chinese Medicine of Guangxi Health Department (GZPT13-45), Guangxi Distinguished Experts Special Fund, Project supported by the Guangxi culture of new century academic and technical leader of special funds; Guangxi Health and Family Planning Commission “139” Leading Talents Training Plan.
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