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Glucose-regulated protein 58 modulates β-catenin protein stability in a cervical adenocarcinoma cell line
- Chia-Jung Liao†1,
- Tzu-I Wu†1, 2,
- Ya-Hui Huang3,
- Ting-Chang Chang4,
- Chyong-Huey Lai4,
- Shih-Ming Jung5,
- Chuen Hsueh5, 6 and
- Kwang-Huei Lin1Email author
© Liao et al.; licensee BioMed Central Ltd. 2014
Received: 19 December 2013
Accepted: 22 July 2014
Published: 1 August 2014
Cervical cancer continues to threaten women’s health worldwide, and the incidence of cervical adenocarcinoma (AD) is rising in the developed countries. Previously, we showed that glucose-regulated protein 58 (Grp58) served as an independent factor predictive of poor prognosis of patients with cervical AD. However, the molecular mechanism underlying the involvement of Grp58 in cervical carcinogenesis is currently unknown.
DNA microarray and enrichment analysis were used to identify the pathways disrupted by knockdown of Grp58 expression.
Among the pathway identified, the WNT signaling pathway was one of those that were significantly associated with knockdown of Grp58 expression in HeLa cells. Our experiments showed that β-catenin, a critical effector of WNT signaling, was stabilized thereby accumulated in stable Grp58 knockdown cells. Membrane localization of β-catenin was observed in Grp58 knockdown, but not control cells. Using a transwell assay, we found that accumulated β-catenin induced by Grp58 knockdown or lithium chloride treatment inhibited the migration ability of HeLa cells. Furthermore, an inverse expression pattern of Grp58 and β-catenin was observed in cervical tissues.
Our results demonstrate that β-catenin stability is negatively regulated by Grp58 in HeLa cells. Overexpression of Grp58 may be responsible for the loss of or decrease in membranous β-catenin expression in cervical AD.
Cervical cancer is the third leading cause of cancer-related mortality among women worldwide , although records show a marked decline in incidence over the past three decades. Despite a reducing in the incidence of cervical squamous cell carcinoma (SCC), the frequency of cervical adenocarcinoma (AD) is increasing due to insufficient detection of cervical AD precursor lesions with the Papanicolaou smear test . Therefore, identification of biomarkers specific for cervical AD is essential for early detection and improved prognosis. Persistent infection with high-risk human papillomavirus (HPV) is the major risk factor for both SCC and AD . However, HPV alone is not sufficient to cause cervical cancer; other molecular markers of cervical carcinogenesis are essential. Previously, we demonstrated that glucose-regulated protein 58 (Grp58) serves as an independent prognostic factor for cervical AD, but not SCC . Cell-based studies revealed that Grp58 regulates the invasion and metastatic ability of HeLa cells. Grp58 is a multi-functional protein belonging to the disulfide isomerase family of proteins . The functions of Grp58 in quality control of glycoprotein and major histocompatibility complex class I (MHC class I) maturation are well documented . Recent evidence has suggested that Grp58 plays a role in cancers [7, 8], although the details are unclear. In the current investigation, we explored the role of Grp58 in cervical AD progression and the molecular mechanism underlying Grp58 function.
Pathway enrichment analysis
Pathway enrichment analysis of a set of differentially expressed genes upon Grp58 knockdown was performed using the GeneGo MetaCore analysis tool (GeneGo, St. Joseph, MI). Genes displaying differential expression, by comparing stable control and Grp58 knockdown cells, greater than 1.2 fold were uploaded. A pathway map with a false discovery rate of <0.01 was considered significant.
Cell lines and cultures
The human cervical cancer cell line, HeLa, was obtained from the American Type Culture Collection (ATCC, Number: CCL-2), and cultured as recommended. Stable Grp58 knockdown cells were established as described earlier . For MG132 (Sigma-Aldrich, St. Louis, MO) and LiCl (Sigma-Aldrich) treatment, cells were seeded and incubated overnight. The culture medium was refreshed, and MG132 (10 μM) or LiCl (20 or 40 mM) was added to the culture medium at 4 and 24 h prior to harvest, respectively. For the Boyden chamber assay, LiCl was added to the upper and lower chambers during cell seeding. For analysis of β-catenin degradation, cells were pre-treated with MG132 for 4 h. The medium was refreshed and cycloheximide (CHX, 10 ng/ml; Sigma-Aldrich) was used to block new protein synthesis. Cells were harvested at 0, 1, 2, and 4 h after treatment with CHX.
Real-time quantitative RT-PCR (qRT-PCR)
Total RNA was extracted from cells using TRIzol. The first cDNA strand was synthesized using the superscript III kit for RT-PCR (Life Technologies, USA). qRT-PCR was performed using SYBR Green, as described previously . The primer sequences for β-catenin were as follows: forward, 5’-CCg CAA ATC ATg CAC CTT T-3’, and reverse, 5’-CTg ATg TgC ACg AAC AAg CA-3’. Primers used in supplementary data were listed in Additional file 1: Supplementary Methods and Figures.
Western blot analysis
Western blot analysis was performed as described previously . Anti-Grp58 rabbit polyclonal antibody (1:10,000 dilution; Atlas, Sigma-Aldrich, St. Louis, MO), anti-β-catenin mouse monoclonal antibody (1:2000 dilution; E-5 clone; Santa Cruz Biotechnology Inc., Santa Cruz, CA) and horseradish peroxidase-conjugated, affinity-purified secondary antibody to rabbit or mouse (Santa Cruz Biotechnology) were used. Immunocomplexes were visualized via chemiluminescence with an ECL detection kit (Amersham, Piscataway, NJ).
Cells were trypsinized and re-suspended using serum-free medium. Equal amounts of cells (5×104 in 100 μl) were seeded in the upper chamber (Corning-Costar 3494 Transwell, Lowell, MA) in triplicate. Lower chambers were supplemented with 20% fetal bovine serum in medium. Traversed cells were stained with crystal violet after 24 h incubation.
Immunofluorescence (IF) staining
Cells were seeded on glass slides, fixed with 3.7% paraformaldehyde, permeabilized with 0.1% Triton X-100/PBS (PBST) for 10 min, blocked with 1% bovine serum albumin for 30 min, and stained with the indicated primary antibody for 3 h at RT. After washing three times with PBST, slides were incubated with secondary antibody for 2 h at RT. Fluorescence images were acquired using confocal microscopy (ZEISS LSM 510 META, Carl Zeiss Inc., Oberkochen, Germany). Grp58 and β-catenin primary antibodies were the same as those used for Western blotting. The secondary antibodies employed were Alexa Fluor 488 goat-anti-mouse and 568 goat-anti-rabbit antibody (Invitrogen Co., Carlsbad CA).
Immunohistochemistry (IHC) staining
Formalin-fixed and paraffin-embedded tissues were examined using IHC, according to previously described procedures . The Grp58 (Atlas, 1:2000 dilution) and β-catenin (Santa Cruz Biotechnology, Inc., Santa Cruz, CA; 1:100 dilution) antibodies were used, along with horseradish peroxidase-conjugated anti-rabbit and anti-mouse secondary antibodies (Santa Cruz). Immunocomplexes were visualized using the Envision kit (DAKO, Carpinteria, CA). Brown-colored cytoplasmic patches were considered Grp58-positive. Slides were scored separately by two independent pathologists (Y.L and S.M.J) blinded to all clinical data. Staining intensity was graded as absent (0), weak (1+), medium (2+) or strong (3+). The histoscore (Q) was calculated by multiplying the percentage (P) of positive cells by intensity (I), according to the formula: Q = P × I. The mean Q of each cervical cancer type was selected as the cut-off value to divide the high/low expression groups, as described previously.
Data from a total of 109 cervical carcinoma patients subjected to primary definitive surgery between 2000 and 2008 at Chang Gung Memorial Hospital (Taoyuan, Taiwan) were retrieved from the hospital database, and the histological types confirmed by pathologists. Thirty-four patients with cervical AD, classified as stage I to IIB according to the International Federation of Gynecology and Obstetrics (FIGO) staging system, were enrolled under the protocol approved by the Institutional Review Board (IRB: 95-1241B); all patients provided informed consent. The personal rights of the patients were preserved.
One-way analysis of variance (ANOVA) was used to compare means of more than two groups. Mann–Whitney test was applied to compare the means of two independent groups. P values < 0.05 were considered significant. SPSS statistical software was used for statistical analyses.
Altered WNT signaling pathway in Grp58-knockdown HeLa cells
Pathway map enrichment analysis
Granzyme A signaling
Apoptosis and survival
TGF, WNT and cytoskeletal remodeling
Antigen presentation by MHC class I
IGF-1 receptor signaling
Androgen Receptor nuclear signaling
Glucocorticoid receptor signaling
ATM/ATR regulation of G1/S checkpoint
LRRK2 in neurons in Parkinson's disease
Endothelial cell contacts by junctional mechanisms
Endoplasmic reticulum stress response pathway
Apoptosis and survival
Role of Activin A in cell differentiation and proliferation
WNT signaling pathway. Part 2
WNT signaling pathway. Part 1. Degradation of beta-catenin in the absence WNT signaling
TGF-beta-dependent induction of EMT via SMADs
Grp58 regulates β-catenin protein stability
β-catenin accumulates in cell-cell adherens of Grp58-knockdown HeLa cells
β-catenin inhibits HeLa cell migration
Inverse expression patterns of Grp58 and β-catenin are observed in cervical cancer
β-Catenin is a protein with ambivalent functions. It serves as an adherent molecule to maintain epithelial phenotype of cell thereby inhibiting cell invasiveness. On the other hand, it is found in the nucleus together with LEF-1 transcription factor to drive a variety of target genes, such as epithelial-mesemchymal transition regulated genes, thereby enhances cell invasiveness [22, 23]. The present study of Grp58 regulation of cell invasiveness in cervical AD demonstrated that β-catenin is stabilized thereby accumulates in the membrane in Grp58 knockdown HeLa cells, thereby inhibiting migration ability. To our knowledge, this is the first study to provide evidence that Grp58 regulates WNT signaling. In our microarray experiment, several genes downstream of the WNT canonical pathway were identified. However this phenomenon appears to reflect a nuclear rather than a plasma membrane adherent function of β-catenin. Indeed, membrane-targeted β-catenin has been shown to increase the concentration of cytosolic β-catenin, which is necessary for transduction signals to the nucleus . Nuclear β-catenin is thought to play an oncogenic role in tumorigenesis. However, earlier studies suggest that some potent invasion-promoting genes, such as S100A4 and NEDD9, are inhibited by the WNT canonical pathway . Shtutman et al. demonstrated that induction of progressive multifocal leukoencephalophthy by β-catenin suppresses the tumorigenicity of renal carcinoma cells . Microarray analysis led to the identification of S100A4 as a downregulated gene in the current study. The S100A4 protein level was verified using Western blot analysis (Additional file 2: Figure S1B). Decreased S100A4 expression may result in attenuation of migration and invasion abilities. However, restoration of S100A4 expression was not sufficient to rescue the migration and invasion phenotype (data not shown). Identification of the key molecules involved in Grp58-β-catenin-mediated regulation of cell invasiveness is thus of considerable interest.
Abnormal β-catenin expression, observed as loss of or reduced membranous staining, is a common feature of cervical cancer [21, 27], and alterations in β-catenin-related cell adherence are thought to be involved in cervical carcinoma pathogenesis . In our study, all β-catenin positive staining cases shown a membranous fashion and nuclear staining of β-catenin was not observed in any cases. This result is identical with previous studies in cervical AD [20, 21]. β-Catenin function as a transcription activator may prefer to be an adhesion molecule in early stage cervical AD. Therefore, the accumulated β-catenin induced by Grp58 depletion or LiCl appears to play the adherent role and inhibited HeLa cell invasiveness. In our study population, membranous β-catenin was significantly decreased in a large proportion of AD tissues, compared to adjacent normal epithelium, which served as the normal control since the adjacent normal columnar epithelium was rarely observed on the tissue slide. Conversely, Grp58 was overexpressed in AD. We observed inverse expression patterns of Grp58 and β-catenin in our clinical specimens as well as a commercial TMA. In the cell-based study, knockdown of Grp58 expression resulted in accumulation of β-catenin around the plasma membrane of cells. Based on these results, we speculated that Grp58 acts as a regulator of β-catenin protein distribution and stability in cancer cells.
A previous study by our group demonstrated that Grp58 serves as an independent factor for cervical AD but not SCC . Accordingly, we investigated the role of Grp58 in the cervical AD cell line HeLa. A migration assay was additionally performed with Caski and C33A, two SCC cell lines with Grp58 knockdown, as well as control cells without Grp58 knockdown. Migration abilities were moderately affected in the Grp58 knockdown cell lines, compared to control cells (Additional file 4: Figure S3). The regulatory effect of Grp58 on cell migration may thus be more significant in AD than SCC.
One of the most widely studied functions of Grp58 is its role in the immune system. Grp58 participation in MHC class I antigen presentation is well documented . Consistent with this, the “Antigen presentation by MHC class I” pathway was the third most significantly enriched in our microarray analysis. Alterations in adaptive immune responses have been reported in cervical cancer . Additionally, Cromme et al. demonstrated that MHC class I is downregulated in metastases from cervical carcinoma compared with the primary tumors . Therefore, we speculated that Grp58 regulates the adaptive immune response to augment cancer invasion. Granzyme A (GZMA) signaling was the most significantly affected pathway in our enrichment analysis which is mainly attributed to differential expression of SET complex, the central component in the GZMA pathway (Table 1 and ref. ). Four members of the SET complex, including SET, high mobility group box 2 (HMGB2), APEX nuclease 1 (APEX1) and acidic leucine-rich nuclear phosphoprotein 32 family member A (ANP32A), are affected by Grp58 silencing . SET complex responses to GZMA and oxidative stress represents in tumors to regulate cell apoptosis . Downregulation of homeostatic ER stress responses via knockdown of Grp58 expression appears to enhance apoptosis induced by oxidative stress-inducing drugs . Accordingly, knockdown of Grp58 expression may disrupt ER homeostasis, resulting in accumulation of oxidative stress and changes in the status of the SET complex. The detailed molecular mechanism underlying Grp58-mediated apoptosis is unclear. It would be of interest to determine whether Grp58 regulates apoptosis through the SET complex and associated proteins that participate in cervical cancer progression and drug resistance.
Patients with cervical AD are generally considered to have a poorer prognosis than those with SCC . However, knowledge of the natural history and optimal management of cervical AD is limited. Early detection, prognosis and treatment strategies specific to AD should be explored in future studies. Previously we identified Grp58 as an independent prognostic marker for cervical AD . Here we have demonstrated that Grp58 appears to regulate WNT signaling by targeting β-catenin to augment cancer invasion. Regulation of the immune response and free radical homeostasis are possible mechanisms underlying cervical cancer progression. Further research is warranted to determine the detailed mechanism of Grp58 action in cervical cancer progression.
This work was supported by grants from Chang-Gung University, Taoyuan, Taiwan (CMRPD 190402) and the Department of Health (DOH99-TD-C-111-006).
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