H-rev107 regulates prostaglandin D2 synthase-mediated suppression of cellular invasion in testicular cancer cells
© Shyu et al.; licensee BioMed Central Ltd. 2013
Received: 18 February 2013
Accepted: 15 May 2013
Published: 20 May 2013
H-rev107 is a member of the HREV107 type II tumor suppressor gene family which includes H-REV107, RIG1, and HRASLS. H-REV107 has been shown to express at high levels in differentiated tissues of post-meiotic testicular germ cells. Prostaglandin D2 (PGD2) is conjectured to induce SRY-related high-mobility group box 9 (SOX9) expression and subsequent Sertoli cell differentiation. To date, the function of H-rev107 in differentiated testicular cells has not been well defined.
In the study, we found that H-rev107 was co-localized with prostaglandin D2 synthase (PTGDS) and enhanced the activity of PTGDS, resulting in increase of PGD2 production in testis cells. Furthermore, when H-rev107 was expressed in human NT2/D1 testicular cancer cells, cell migration and invasion were inhibited. Also, silencing of PTGDS would reduce H-rev107-mediated increase in PGD2, cAMP, and SOX9. Silencing of PTGDS or SOX9 also alleviated H-rev107-mediated suppression of cell migration and invasion.
These results revealed that H-rev107, through PTGDS, suppressed cell migration and invasion. Our data suggest that the PGD2-cAMP-SOX9 signal pathway might play an important role in H-rev107-mediated cancer cell invasion in testes.
KeywordsMurine H-rev107 Human H-REV107 Retinoid-inducible gene 1 Prostaglandin D2 synthase Testis HREV107 type II tumor suppressor
H-rev107 , also called HRASLS3  or PLA2G16 , is a member of the HREV107 type II tumor suppressor gene family, which includes H-REV107, retinoid-inducible gene 1 (RIG1) , HRASLS2 [5, 6], HRLP5 , and HRASLS . The protein in this family contains an NC domain, with unknown function at the N-terminus, and a hydrophobic membrane-anchoring domain at the C-terminus [9, 10]. The family proteins exhibit activities that regulate cellular growth, differentiation, and apoptosis, and the membrane-anchoring domain is indispensable for this activity [11–14].
Human H-REV107 and RIG1 have been shown to be involved in the regulation of cellular growth, apoptosis, and differentiation. RIG1 is expressed in highly differentiated tissue derived from skin and colon [13, 15, 16]. H-REV107 is expressed at high levels in differentiated tissues of post-meiotic testicular germ cells but not in testicular germ cell tumors . Both genes are expressed in normal tissues in a tissue-specific manner and are downregulated in various cancer tissues [15–18]. These proteins exhibit growth-suppressive activities when ectopically expressed in various types of cancer cells and RAS-transformed fibroblasts [6, 8, 11, 13, 19–22]. In addition, terminal differentiation of keratinocytes has been observed in cells with induced RIG1 expression [13, 23]. Therefore, the HREV107 protein family might play an important role in the regulation of cell growth and differentiation in both normal and cancer cells.
Several studies have observed anti-RAS, phospholipid-metabolizing, and enhancing transglutaminase activities among the HREV107 protein family. Murine H-rev107 was first isolated from revertants of HRAS-transformed fibroblasts . Also, H-REV107 and HRASLS were shown to inhibit the RAS-mediated transformation of fibroblasts [8, 20]. Similar inhibition of the RAS signal pathways has been observed in HRASLS2-expressing  or RIG1-expressing cervical and gastric cancer cells . The results of our studies further demonstrated a downregulation of activated RAS and total RAS by RIG1 through the post-translational mechanism [11, 24]. In addition to the inhibition of RAS, the HREV107 family proteins are phospholipid-metabolizing enzymes. H-REV107 catalyzes the efficient release of free fatty acids and lysophospholipid from phosphatidylcholine, indicating that it acts as phospholipase A . Also, different HREV107 family members catalyze particular phosphatidylcholines or phosphatidylethanolamines [5, 7]. In keratinocytes, RIG1 has been shown to stimulate cellular differentiation which is mediated by activating type I tissue transglutaminase [13, 23]. These results suggest that RIG1, HRASLS2, and H-REV107 can regulate cellular differentiation in various tissues through different downstream signal pathways.
Prostaglandin D2 (PGD2), which is synthesized by prostaglandin D2 synthase (PTGDS) in many organs, has been implicated as a signaling molecule in the mediation or regulation of various biological processes. PGD2 is expressed in male mice in the early stages of gonadogenesis . Also, PGD2 is shown to contribute to SRY-related high-mobility group box 9 (SOX9) nucleus translocation, which is a critical step of the Sry-initiated testis-determining cascade . The expression of PTGDS is expressed in the cellular lineage that gives rise to the Sertoli cells , and the Sertoli cells express PTGDS only during the VI-VIII stages of the spermatogenic cycle, immediately after spermiation . The studies support the role of the PGD2/ PTGDS signaling pathway in the regulation of testis tissue differentiation.
The transcriptional factor SOX9 is involved in cell differentiation, growth and invasion. SOX9 is a master regulator of Sertoli cell differentiation during testis development and is the crucial gene to determine sex [26, 29, 30]. SOX9 also plays a role in osteochodrogenenic differentiation . SOX9 expression is upregulated by PGD2, and ectopic SOX9 expression has been shown to suppress growth of ovarian cancer and melanoma cells in vitro and/or in vivo. However, both aberrant SOX9 expression in carcinoma tissues and elevated SOX9 expression are correlated to disease progression and poor prognosis for hepatocellular carcinoma, gastric cancer and prostate cancer [33–35]. SOX9 protein levels are elevated in invasive human uroepithelial carcinoma tissues, which are induced by the activation of epidermal growth factor receptor . Therefore, biological activities of SOX9 appear to be target site specific.
Although high levels of H-REV107 expression in differentiated testes suggest a role of H-REV107 in tissue differentiation, the genuine signaling pathway involved in the H-REV107-mediated cell differentiation of testes remains poorly understood. Our recent study revealed that RIG1 interacted with PTGDS and stimulated PTGDS activity in human testicular NT2/D1 cells . RIG1 is expressed in the human species only, whereas H-REV107 is expressed in both human and murine and exhibits high expression levels in human testes . Since H-rev107 and RIG1 belong to the same protein family, we postulated that the binding of RIG1 to PTGDS might exist between H-rev107 and PTGDS. The present results confirmed the binding between H-rev107 and PTGDS, and demonstrated that the H-rev107-mediated suppression of cell invasion was mediated through the enhancement of PTGDS activity in the murine in testes. Our results suggest that the PGD2 pathway might play an important role in the regulation of H-REV107-mediated testis cell differentiation.
Construction of expression vectors
The H-rev107 and PTGDS cDNA fragments were amplified from mouse TM4 testis cancer cells (Bioresource Collection and Research Center [BCRC], Hsinchu, Taiwan) using H-rev107-specific primers (sense, 5’-TCCTCGAGCTATGCTAGCACCCATACCAGAACCC-3’ and antisense, 5’-TCGGATCCTTGCTTCTGTTTCTTGTTTCTGGAGAGCATG-3’) and PTGDS-specific primers (sense, 5’-TCAAGCTTCGATGGCTGCTCTTCGCATGCTGTG-3’ and antisense, 5’- TCGGATCCGCTCTTGAATGCACTTATCCGGTTGG -3’). To generate pH-rev107-myc and pDsRed-H-rev107, the amplified H-rev107 cDNA fragment was digested with Xho I and Bam HI and then subcloned in-frame into the multicloning site of the pcDNA3.1-myc-his A expression vector (Invitrogen, Carlsbad, CA, USA) or pDsRed-C1 (Clontech Laboratories, Inc, Palo Alto, CA, USA). To generate pPTGDS-Flag and pEGFP-PTGDS, the amplified PTGDS cDNA fragment that had been digested with Hin dIII-Bam HI was cloned in-frame into the pPCR3.1-Flag (Dr. Yi-Ling Lin, Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan) and pEGFP-C1 (Clontech Laboratories). The cDNA sequences of fusion proteins were confirmed by DNA sequencing.
Testes tissue sections from Balb/c mice were deparaffinized with trilogy (Cell Marque, Rocklin, CA, USA) and rehydrated in a graded series of ethanol. To retrieve antigens, the sections were boiled for 30 min in 10% DAKO Chem-Mate™ solution (DAKO Co., Carpinteria, CA, USA) containing 0.05% Nonidet P-40. Endogenous peroxidase activity was blocked by incubation in 3% hydrogen peroxide for 10 min. The sections were then incubated at room temperature for 2 h in H-REV107 (Biorbyt, Cambridge, Cambridgeshire, UK), PTGDS (Santa Cruz Biotechnology, Santa Cruz, CA, USA), or control rabbit IgG antibody (Santa Cruz Biotechnology) diluted at 1:1000, 1:200, or 1:400 respectively in DAKO antibody diluent. The DAKO LSAB® 2 Peroxidase kit was used to stain protein expression in tissue sections. Sections were incubated with 3-3’-diaminobenzidine chromogen solution (DAKO Co) for 5 min to reveal the peroxidase complex. Finally, sections were lightly counterstained with Mayer’s hematoxylin (Merck, Darmstadt, Germany) and mounted with DPX mounting medium (Schrlau, Spain). Our study had been reviewed and approved by the Buddhist Tzu Chi General Hospital-Taipei Branch Institutional Animal Care and Use Committee.
Cell culture and transfection
Mouse TM3 mouse Leydig and TM4 mouse Sertoli cells (BCRC) were maintained in a growth medium consisting of a 1:1 mixture of Ham’s F12 medium and Dulbecco's Modified Essential Medium (DMEM) supplemented with 4.5 g/L glucose, 2.5 mM L-glutamine, 0.5 mM sodium pyruvate, 1.2 g/L sodium bicarbonate, 15 mM HEPES, 5% horse serum, and 2.5% fetal bovine serum (FBS). Human NT2/D1 teratocarcinoma cancer cells were maintained in DMEM supplemented with 25 mM HEPES, 26 mM NaHCO3, 2 mM L-glutamine, penicillin (100 units/mL), streptomycin (100 μg/mL), and 10% FBS at 37°C in 5% CO2. Cells plated in culture dishes were transfected with the expression vectors using liposome-mediated transfection. Plasmids and lipofectamine 2000 (Gibco BRL, Gaithersburg, MD, USA) were diluted in Opti-MEM medium and then mixed with plasmids at room temperature for 15 min. The DNA–lipofectamine complexes were then added to cells for 5 h at 37°C. Cells were refreshed with complete medium for 24 h at 37°C for further analysis.
Immunoprecipitation and Western blotting
Cells were lysed in IP lysis buffer (20 mM Tris-HCl at pH 7.5, 100 mM NaCl, 1% Nonidet P40, 100 μM Na3VO4, 50 mM NaF, and 30 mM sodium pyrophosphate) containing 1× complete protease inhibitor cocktail (EDTA-free) (Roche Diagnostics, Mannheim, Germany). Cell lysates containing 500 μg of protein were first incubated first with 3.2 μg of anti-myc (Invitrogen) or 1 μg of anti-Flag-M2 (Sigma, St. Louis, MO, USA) monoclonal antibody for 2 h at 4°C and then incubated with 20 μL of protein G plus /protein A agarose (Calbiochem, Cambridge, MA, USA) at 4°C for 2 h. Immunoprecipitated complexes were washed three times with IP lysis buffer and then analyzed by Western blotting using an anti-myc or anti-Flag antibody. For Western blotting, proteins (20–50 μg) were separated on 12% polyacrylamide gels and transferred to polyvinylidene difluoride membranes. After blocking, membranes were incubated with anti-myc, anti-Flag, anti-PTGDS (Abcam, Cambridge, UK), anti-phospho-SOX9 (Abcam), anti-SOX9 (Abcam), anti-E-cadherin (Santa Cruz Biotechnology, Santa Cruz, CA, USA), anti-vimentin (Santa Cruz Biotechnology), or anti-actin (Sigma) antibody for 12 h at 4°C and then incubated with horseradish peroxidase-conjugated goat anti-mouse or anti-rabbit antibody at room temperature for 1 h. An ECL kit (Amersham, Bucks,UK) was used to detect the substrate reaction.
Confocal and immunofluorescent analysis
TM4 cells (1 × 105) were plated on poly-L-lysine-coated coverslips in 35-mm dishes in growth medium. Cells were then transfected with 500 ng of DsRed-H-rev107 along with 500 ng pEGFP-PTGDS expression vector for 18 h. The cells were washed, fixed with 4% paraformaldehyde, stained with 1 μg/mL 4’6-diamidino-2-phenylindole (DAPI), and then analyzed with a Leica TCS SP5 scanner (Leica, Bensheim, Germany). The fluorescent images were then processed with Image-Pro Plus 5.1 image analysis software.
Measurement of PGD2 and cAMP levels
Cells were cultured onto 6-well plates overnight and then transfected with 500 ng of pPTGDS-Flag along with 500 ng of pH-rev107-myc, or control vector in complete medium for 5 h. Cells were incubated in complete medium supplemented with 1 mM Br-cAMP or ethanol vehicle for 18 h. Alternatively, cells were washed and then incubated with 1 μg/mL arachidonic acid (AA, Sigma) for 1 h or PGD2 (500 ng/mL) for 30 min immediately before harvest. After washing twice with PBS, cells were lysed with 0.1 N HCl for 20 min, scraped, and collected by centrifugation. Levels of PGD2 or cAMP in the supernatants were determined using a prostaglandin D2 express or cyclic AMP EIA kit (Cayman Chemical, Ann Arbor, MI, USA) according to the manufacturer's instructions.
Cell migration and invasion assay
For cell migration assay, NT2/D1 cells (2 × 104) were added to the upper polycarbonate membrane insert (8 μm pore size; Falcon, Becton, Dickinson and Company, Franklin Lakes, NJ, USA) of the cell migration assay kit in a 24-well plate. In the lower well, seven hundred μL of DMEM supplemented with 20% FBS was used as chemoattractant. After 24 h of incubation, cells were methanol fixed for 10 min at room temperature and then stained for 30 min at room temperature with a 50 μg/mL solution of propidium iodide (Sigma).
Polycarbonate-membrane inserts coated with 30 μg Matrigel (BD) were used for cell invasion assays. NT2/D1 cells (2 × 104), suspended in DMEM medium containing 10% NuSerum (BD), were seeded in the membrane insert. Seven hundred μL of serum-containing medium supplemented with PGD2 (500 ng/mL) or ethanol vehicle was placed in the lower chambers, with the medium changed daily for 72 h at 37°C. Cells were fixed and stained for propidium iodide. The number of cells on each membrane was counted under a microscope at a magnification of 40×. Experiments were performed at least twice, and each sample was assayed in triplicate.
Viruses and transduction
LacZ, PTGDS, and SOX9-shRNA-containing lentiviral vectors were obtained from the National RNAi Core Facility (Academia Sinica, Taiwan) and prepared in accordance with standard protocols. Cells were infected with lentivirus (multiplicity of infection 5) in medium containing polybrene (8 μg/mL). Two PTGDS shRNAs targeted to nucleotides 540 to 560 (5’-CAGGGCTGAGTTAAAGGAGAA-3’) and 625 to 645 (5’-GATAAGTGCATGACGGAACAA-3’) were synthesized based on Genbank accession NM_000954. Two SOX9 shRNAs targeted to nucleotides 1761 to 1781(5’-GATAAGTGCATGACGGAACAA-3’) and 3680 to 3700 (5’-GCATCCTTCAATTTCTGTATA-3’) were synthesized based on Genbank accession NM_000346.
Rac activation assays
Cells grown to 80% confluence in 10-cm culture dishes were first transfected with 5 μg H-rev107 or control expression vector and then incubated with 500 ng/mL of PGD2 or ethanol vehicle for 24 h. Cells were serum starved for 12 h and then stimulated with 50 ng/mL epidermal growth factor (EGF, Sigma) for 5 min at 37°C. Rac1 activity was assessed using the Rac1 activation assay kit (Millipore, Temecula, CA, USA). Briefly, cells were washed twice with ice-cold PBS and then lysed in 0.5 mL MLB buffer (25 mM HEPES, pH 7.5, 150 mM NaCl, 1% Igepal CA-630, 10 mM MgCl2, 1 mM EDTA, and 10% glycerol) containing protease inhibitors and phosphatase inhibitors. Cellular lysates containing 300 μg protein were then incubated with 10 μL of the PAK-1 PBD agarose bound with glutathione S-transferase fusion protein corresponding to the human p21 binding domain (PBD, residues 67–150) of human PAK-1 at 4°C for 1 h. After washing three times with MLB containing protease and phosphatase inhibitors, presence of the activated Rac1 (Rac1-GTP) was detected by Western blotting using an anti-Rac1 monoclonal antibody (Millipore).
Expression of H-rev107 and PTGDS in mouse testes
H-rev107 associates and co-localizes with PTGDS
H-rev107 enhances PTGDS activity in human NT2/D1 testis cancer cells
H-rev107 suppresses NT2/D1 cell migration and invasion
PGD2, cAMP, and SOX9 induction by H-rev107 was mediated through PTGDS
H-rev107 suppresses cell migration and invasion through PTGDS
H-rev107 suppresses Rac1 activation and increases E-cadherin expression
Based on the results from the present and our previous  studies, both RIG1 and H-rev107 can interact with PTGDS in testis cells. The interaction enhances PTGDS activity, which increases PGD2 levels, elevates or activates downstream PGD2 signaling molecules like cAMP and phosphorylated SOX9, and suppresses cell migration and invasion. Both PTGDS and SOX9 shRNAs profoundly alleviated RIG1-, H-rev107-, and PGD2-mediated inhibition of cell migration and invasion. Therefore, the mechanism by which HREV107 family proteins attenuate the migration and invasion of NT2/D1 cells is primarily mediated through the activation of PTGDS and the production of PGD2.
PGD2 has been shown to inhibit cell migration and invasion. PGD2 inhibits the migration of airway dendric cells and epidermal Langerhans cells to the draining lymph nodes, and the inhibition is mediated through prostanoid receptor 1 [39, 40]. Similar inhibition of cell migration by PGD2 is also observed in eosinophils, basophils and lung fibroblasts [41, 42]. PGD2 inhibited cell invasion, whereas PGE2 stimulated invasion of PC-3 prostate cancer cells . Also, PGD2 levels in primary colorectal carcinoma tissues without liver metastasis are shown to be significantly lower than that with hepatic metastasis . The results agree with the inhibition of cell migration and invasion in NT2/D1 testis cancer cells followed by PGD2 treatment or the ectopic expression of RIG1 or H-rev107 shown in this and our previous studies . Epithelial-mesenchymal transition and elevated Rac activities have critical roles in cellular motility and migration. PGD2 is shown to inhibit TGF-β1-induced epithelial-mesenchymal transition by increasing E-cadherin in MDCK cells . Similarly, an increase in expression of E-cadherin and a decrease in expression of mesenchymal marker protein vimentin and in Rac 1 activation were observed in NT2/D1 cells that expressed H-rev107. These results confirmed the invasion-suppression capacity of H-rev107 in testes cells. SOX9 is shown to be required in migration and in invasion of uroepithelial carcinoma cells in vitro, and upregulation of SOX9 is related to the progression of prostate and gastric cancers [33–35]. However, we observed that knockdown of PTGDS or SOX9 expression effectively alleviated both RIG1  and H-rev107-mediated inhibition of cell migration and invasion in testis cancer cells. The difference in the activities of SOX9 in cell migration and invasion might be attributable to the tissue specific effects of the protein.
The PGD2-SOX9 signal pathway is important in testis development . PDG2 induces nuclear import of SOX9 that subsequently induces Sertoli cell differentiation . The facts that the increase in PGD2 production and SOX9 expression through PTGDS activation in H-rev107 and RIG1 transfected NT2/D1 cells shown in this and our previous  studies support pro-differentiation activities of both RIG1 and H-rev107 in testis cancer cells. This is consistent with the finding that only terminal differentiated testis tissues appear to contain murine H-rev107, human HREV107  and PTGDS. Results from this and our previous  studies demonstrated similar biological activities between RIG1 and H-rev107 in the activation of PTGDS that subsequently increase the level of PGD2 and SOX9 and inhibit cell migration and invasion. Whether the activities described above differ in potency between RIG1 and H-rev107 remains unclear. A side-by-side comparison of RIG1 and H-rev107 expression and downstream signaling pathways will clarify the roles of RIG1 and H-rev107 in testes differentiation and in the inhibition of testis cell invasion.
Previous studies have shown that the HREV107 family proteins exhibit tumor suppressor activities in combination with various target proteins. In cervical cancer, RIG1 suppresses cell growth and induces cell death through caspase-dependent and -independent pathways [12, 24]. In skin cancer, RIG1 induces cell apoptosis by promoting pericentrosomal organelle accumulation, which is associated with the decrease in cyclin D1, cyclin E, and Bcl-XL and the increase in p21 and Bax levels [22, 46]. In addition, both RIG1 and H-REV107 have been suggested to exhibit phospholipase A(1/2) activity [3, 5], which is involved in H-rev107-mediated HEK cell death by regulating peroxisomal lipid metabolism . However, pro-apoptotic activity of H-REV107 has not been observed in testis cells. The use of phospholipase A(1/2) inhibitor cannot alleviate the RIG1-mediated suppression of cell invasion . These results reveal that the targeted effects for the HREV107 family proteins vary by cell type.
Aside from the difference in targeted proteins for H-REV107, subcellular localization of H-REV107 would be considered as an important factor that might have impact on cell function. Nuclear targeted H-REV107 has been shown to stimulate cell growth of non-small cell lung carcinomas . In contrast, nuclear targeted H-REV107111–123 and RIG1111–123 peptides induce profound proapoptotic activities in cancer cells [12, 49]. Results from most studies have revealed that the HREV107 family proteins are expressed in the perinuclear region [6, 13, 14, 23, 24]. Perinuclear localization of RIG1 has been shown to inhibit expression or activation of signaling molecules such as HER2, RAS, PI3K/AKT, mTOR, and type I transglutaminase that are involved in the regulation of cell growth, apoptosis, tumor invasion, and cell differentiation [11–13, 24, 50]. The downstream signal transduction pathways involved in RIG1-mediated cell function are dependent on the cell type and the binding effectors. For example, the transglutaminase inhibitor monodansylcadaverine can suppress RIG1-mediated terminal differentiation of keratinocytes . However, the compound is not able to inhibit RIG1-mediated RAS suppression and induce cell death of cervical cancer cells (data not shown).
Results from this and our previous studies  support the roles of RIG1/H-rev107 in testis cell invasion/migration. However, a signal cascade involving RIG1/H-rev107-PTGDS-SOX9 has also been implicated in testis development and differentiation based on results from this and previous [17, 26] studies. Due to the lack of sex-differentiation marker like Mullerian hormone and Sertoli cell marker  in cell line culture, an organ culture of testis with Sertoli cells that support spermatogenesis at various stages of cell differentiation will be used in our future studies. Also, analysis of H-rev107 in the sex-determining cascade in ex vivo using H-rev107 knockout mice will be helpful in identifying the signal responsible for H-rev107-mediated testis development.
In conclusion, H-rev107 and PTGDS are both highly expressed in differentiated spermatids in normal testis tissues. H-rev107 exhibited invasion-suppressive activity in testis cancer cells. PTGDS is essential for H-rev107-mediated production of PGD2, cAMP, and SOX9. Furthermore, reduction of PTGDS or SOX9 alleviates the H-rev107 mediated suppression of cell migration and invasion. Further analysis of H-rev107 in gene knockout mice will be useful to pinpoint the role of H-rev107 in testis development.
Dulbecco’s modified essential medium
Fetal bovine serum
Prostaglandin D2 synthase
Retinoid-inducible gene 1
SRY-related high-mobility group box 9.
This work was supported by grants from the National Science Council (NSC 101-2311-B-303 -001) and the Buddhist Tzu Chi General Hospital, Taipei Branch (TCRD-TPE-102-17). The authors thank the Core Laboratory of the Buddhist Tzu Chi General Hospital Taipei Branch for facility support.
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