Effect of resveratrol on cancer progression through the REG Ⅲ expression pathway in head and neck cancer cells
- Authors:
- Published online on: August 19, 2016 https://doi.org/10.3892/ijo.2016.3664
- Pages: 1553-1560
Abstract
Introduction
Worldwide, >600,000 people are newly diagnosed with head and neck cancer each year (1–3), and head and neck squamous cell carcinoma (HNSCC) is one of the 10 most common malignancies in the world and also known for clinical progression and poor prognosis. The cancer-related death is mainly caused by metastasis of tumors to regional lymph nodes and distant organs. Many patients are diagnosed in advanced stages, in which standard treatment is a combination of platinum-based chemotherapy, radiation, and/or surgery (3–6). As primary treatments for advanced HNSCC, recently there have been advances in definitive chemoradiotherapy (CRT) instead of extended surgery. Despite the recent progress of the treatment for improving locoregional control in HNSCC patients, that for recurrence and metastatic control remains insufficient (7,8), indicating that there is a continued need for improved treatment strategies. As an obvious risk factor of HNSCC, continuous irritation by tobacco and alcohol abuse is well-known (3,7,9). Furthermore, recent studies have shown that HNSCC is associated with human papillomavirus (HPV) infection, especially at oropharyngeal region (10–12). In contrast, there is no reliable marker for the other sites of HNSCC. Therefore, the key molecules that enhance chemo- and radiosensitivity in HNSCC and identification of reliable markers for predicting the recurrence and metastasis would be desirable to improve the prognosis of HNSCC patients.
It has been reported that inflammation is an important phase in tumor progression, and many cancers originate from inflammation. In connection with digestive organs, many studies have demonstrated that the human regenerating gene (REG) expression is observed in chronic inflammation and in tumors (13–20). Reg was first identified in regenerating pancreatic islets in 1988 (21). Reg family belongs to the lectin superfamily and encodes five small, secreted proteins (13,22–25). Reg family proteins are classified into four subfamilies: type I, II, III, and IV; the human REG family consists of five members: REG Iα, REG Iβ, REG III, hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) and REG IV (13,20,22,26–29). REG family protein has been shown to play roles, not only in normal tissue regeneration (30,31), but also in the development of various malignancies (32–43). Indeed, REG expression has been reported to be associated with progression of cancers such as esophageal, gastric, lung, and colorectal cancer (32–39,43). Considering that oral and pharyngeal cavities are often exposed to chronic inflammatory factors such as tobacco, alcohol and mechanical stimuli, it is possible that REG expression is associated with HNSCC. Recently we reported that REG III expression was associated with prognosis of HNSCC patients (44). In addition, we demonstrated that REG III regulated cell proliferation and chemo- and radiosensitivity in HNSCC in vitro. These results suggested that enhancement of REG III expression increased chemo- and radiosensitivity, and improved prognosis of HNSCC patients. In the present study, we investigated the stimulator for the enhancement of REG III expression in HNSCC cells. Furthermore, we first demonstrate that the stimulator can effect proliferation, invasion, and chemo- and radiosensitivity in HNSCC cells.
Materials and methods
Cell culture and reagents
Human HNSCC cells, FaDu and HSC-4, were employed in this study. FaDu cells were provided by the American Type Culture Collection (Manassas, VA, USA). HSC-4 cells were obtained from the Japanese Cancer Research Resources Bank (Tokyo, Japan). The cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM; Invitrogen, Grand Island, NY, USA) supplemented with 10% fetal bovine serum (FBS; Gibco, Grand Island, NY, USA) and 100 U/ml penicillin G and 100 μg/ml streptomycin and 250 ng/ml amphotericin B (Gibco™ Antibiotic-Antimycotic; Gibco). The cells were maintained in a 5% CO2/95% air, humidified atmosphere at 37°C. Interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) were purchased from Roche Applied Science (Indianapolis, IN, USA). IL-1β, IL-8, IL-11, IL-13, IL-17, IL-22, hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), cardiotrophin, oncostatin M, interferon (IFN)-β, quercetin, 3,4′,5-trihydroxy-trans-stilbene (resveratrol), fisetin, genistein, chlorogenic acid, estradiol, bisphenol A, sodium butyrate were obtained from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Dexamethasone (Dx) and o-dianisidine were from MP Biomedicals (Santa Ana, CA, USA). Daidzein was purchased from Fujicco Co., Ltd. (Kobe, Japan), epigallocatechin gallate from Enzo Life Sciences, Inc. (Framingdale, NY, USA), curcumin from Nacalai Tesque, Inc. (Tokyo Japan), ciglitazone and troglitazone from Cayman Chemical Co. (Ann Arbor, MI, USA), trichostatin A from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan), and phorbol 12-myristate 13-acetate from Sigma-Aldrich (St. Louis, MO, USA).
Isolation of stable transformants with REG III promoter vector
The reporter constructs were prepared by inserting the 5′-flanking regions of human REG III (−1,985 to +87 of REG III gene) (28) upstream of a luciferase reporter gene in pGL4.17 vector (luc2/Neo; Promega Corp., Madison, WI, USA). The REG III promoter vector was introduced into FaDu cells by electroporation using Gene Pulser Xcell™ (Bio-Rad, Hercules, CA, USA) (44), after which the stable transformants were selected in DMEM supplemented with 10% FBS and 500 μg/ml Geneticin® (Invitrogen) for 3 weeks. Introduction of the REG III promoter/luciferase construct in the Geneticin®-resistant cells was confirmed by PCR.
Promoter assays
The REG III promoter vector was introduced into FaDu cells as described above. The stable transformants were seeded in 24-well plates at an initial density of 1×105 cells/well. After a 24-h incubation, the cells were treated with 20 ng/ml of IL-1β, 20 ng/ml of IL-6, 10 nM of IL-8, 100 ng/ml of IL-11, 100 ng/ml of IL-13, 1 μg/ml of IL-17, 20 ng/ml of IL-22, 50 ng/ml of HGF, 10 nM of bFGF, 10 nM of EGF, 20 ng/ml of TNF-α, 20 ng/ml of cardiotrophin, 20 ng/ml of oncostatin M, 100 nM of Dx, 50 ng/ml of IFN-β, 50 μM of quercetin, 20 μM of resveratrol, 20 μM of fisetin, 50 μM of genistein, 60 μM of chlorogenic acid, 200 μM of o-dianisidine, 10 nM of okadaic acid, 10 μM of daidzein, 100 nM of epigallocatechin gallate, 1 μM of estradiol, 10 μM of bisphenol A, 12.5 μM of curcumin, 50 μM of ciglitazone, 30 μM of troglitazone, 1 μM of trichostatin A, 1 mM of sodium butyrate, or 50 nM of phorbol 12-myristate 13-acetate. After a 24-h treatment, the medium was aspirated from each well and washed with PBS, and the cells were harvested with 100 μl of lysis buffer (0.1 M potassium phosphate, pH 8.8, 0.2% Triton X-100). The cells were processed for luciferase assay using a Pica Gene luminescence kit (TOYO B-Net Co., Ltd., Tokyo, Japan) as described (45–50).
Quantitative real-time RT-PCR
Total RNA was isolated using RNeasy Protect® Cell Mini Kit (Qiagen, Hiden, Germany) from FaDu cells. cDNA was reverse transcribed from 0.5–2 μg samples of total RNA using High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA, USA) as described (44,45,47–51). cDNA was subjected to PCR with the following primers, synthesized and prepared by Nihon Gene Research Laboratories, Inc. (NGRL; Sendai, Japan): β-actin (NM_001101) sense, 5′-GCGAGAAGATGACCCAGA-3′ and antisense, 5′-CAGAGGCGTACAGGGATA-3′; REG III (AB161037) sense 5′-GAATATTCTCCCCAAACTG-3′ and antisense, 5′-GAGAAAAGCCTGAAATGAAG-3′.
Real-time PCR was performed using KAPA SYBR FAST qPCR Master Mix (Kapa Biosystems, Boston, MA, USA) and Thermal Cycler Dice Real-Time System (Takara Bio, Inc., Otsu, Japan) as described (43–45,47–51). PCR was performed with an initial step of 3 min at 95°C followed by 40 cycles of 3 sec at 95°C, 20 sec at 60°C. The level of target mRNA was normalized to the mRNA level of β-actin as an internal standard.
Cell proliferation assay
Cell proliferation activity was assessed by using a Cell Counting Kit-8 [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt (WST-8) cleavage; Dojindo Laboratories, Kumamoto, Japan] as described (43,44,47,50,52). Cells were plated in 96-well plates and incubated for 24 h. Initial density of FaDu and HSC-4 cells was 3×103 cells/well. After 24 h, 30 μM of resveratrol was added to each well and incubated for 24, 48 and 72 h, while dimethylsulfoxide (DMSO; Sigma-Aldrich) was added as a control. At 24 h of incubation, medium was changed and resveratrol was removed from each well. After addition of 10 μl of WST-8 solution, the cells were incubated for another 2 h. The absorbance of each well at 450 nm (reference wavelength at 620 nm) was read by using a Multiskan™ FC Microplate Photometer (Thermo Fisher Scientific, Waltham, MA, USA). Each measurement was repeated at least four times on each cell line.
Chemo- and radiotherapy for cultured cells
Cells were exposed to 0, 5 and 10 Gy radiation using a MBR-1520R (Hitachi, Ltd., Tokyo, Japan) operating at 150 kV and 20 mA as described (44), which delivered the dose at 0.8 Gy/min. Chemotherapy involved the application of cisplatin (Nihon Kayaku Co., Tokyo, Japan) to the cultures at a concentration of 0, 1.0, 3.0 or 10 μM as described (44).
As for chemo- and radiosensitivity, the cell viability was assessed using WST-8 cleavage. Cells were plated in 96-well plates and incubated for 24 h. Initial density of FaDu cells was 3×103 cells/well, and of HSC-4 cells 1×103 cells/well. After 24 h, 30 μM of resveratrol were added to each well, while DMSO was added as a control, and incubated for 48 h. For radiotherapy, they were then irradiated at 0, 5, or 10 Gy respectively. For chemotherapy, cisplatin (0–10 μM) was added to cultures. Following incubation for additional 72 h, the absorbance of each well at 450 nm (reference wavelength at 620 nm) was read as described above. Each measurement was repeated at least four times on each cell line.
Invasion assay
Invasion assays were performed using 24-well Matrigel-coated Transwells (BD Biosciences, Bedford, MA, USA). A total of 4×104 cells of FaDu and HSC-4 were suspended in 200 μl of serum-free DMEM and placed in the top chambers, and 700 μl of DMEM containing 10% FBS were added to the bottom chambers. After 48 h of incubation at 37°C, non-invading cells were removed from the top of the Matrigel with a cotton swab, while invading cells on the bottom surface of the filter were fixed in 4% paraformaldehyde and stained with Giemsa (Sigma-Aldrich) for 10 min. The invading cells were then visualized at ×200 magnification and counted in five fields for each filter.
Data analysis
Data were expressed as means ± standard error (SE). Statistical significant differences between groups were determined by Student’s t-test using StatMate IV (Abacus Concepts, Berkeley, CA, USA). P<0.05 was considered significant.
Results
Activation of REG III gene promoters in FaDu cells
To investigate activators of REG III gene expression, we tested various stimulative substances in two clones of FaDu cells to which the REG III promoter vector was stably introduced (Fig. 1). Among these various stimulators, polyphenols such as resveratrol, genistein, daidzein, and histone deacetylase inhibitors such as sodium butyrate, significantly increased the REG III promoter activity (Fig. 1). We also tested the concentration-response relationship of resveratrol, genistein, daidzein, sodium butyrate for REG III promoter activation, and found that the optimum concentration was 10 μM (resveratrol), 25 μM (genistein), 40 μM (daizein), and 2 mM (sodium butyrate) (data not shown).
Induction of REG III mRNA by candidate substances in FaDu cells
We examined mRNA levels of intrinsic REG III in FaDu cells by using real-time RT-PCR, after treating cells with 10 μM resveratrol, 25 μM genistein, 40 μM daidzein, and 2 mM sodium butyrate, respectively. Resveratrol significantly increased the mRNA levels of REG III as compared with the others (Fig. 2). The combined addition of resveratrol with other candidates did not enhance, rather inhibited, the increment of REG III mRNA expression by resveratrol alone. It might be due to over-stimulation for the signaling pathway, and as a result, it might be higher concentrations for the effect, as reported by Liu et al (53). We also tested the concentration (0–100 μM)-response relationship of REG III mRNA expression by resveratrol and found that the optimum concentration of resveratrol for REG III expression was 30 μM (data not shown).
Effect of resveratrol on growth inhibition in HNSCC cells
We sought to evaluate the effect of resveratrol on cell proliferation of HNSCC cells, FaDu and HSC-4. In the proliferation assay using WST-8 cleavage, HNSCC cells (both FaDu and HSC-4 cells) treated with 30 μM resveratrol showed a significant decrease in growth compared to untreated cells as a control. The resveratrol-induced growth inhibitory effect in HNSCC cells was time-dependent (Fig. 3).
Resveratrol enhances the chemo- and radiosensitivity of HNSCC cells
We measured the chemo- and radiosensitivity by addition of resveratrol to HNSCC cells using WST-8 cleavage. We found that HNSCC cells treated with resveratrol showed a significant increase in chemosensitivity (3.0 and 10 μM of cisplatin) and radiosensitivity (5 and 10 Gy), as compared with cells treated with DMSO as a control (Fig. 4). Therefore, these results indicated that resveratrol enhances the chemo- and radiosensitivity of HNSCC cells.
Resveratrol blocks cancer invasion of HNSCC cells
We measured the invasive ability by addition of resveratrol to HNSCC cells using an invasion assay. We found that cells treated with resveratrol displayed significantly less invasive ability compared to that of the untreated cells as a control (Fig. 5).
Discussion
REG family proteins are believed to be associated with human digestive diseases such as inflammation and cancer (32–42,44,54,55). Recently, among human REG gene family, we have reported that REG III expression was associated with an improved survival rate for HNSCC patients, and REG III regulated cell proliferation and chemo- and radiosensitivity in HNSCC in vitro (44).
REG proteins are upregulated in many human cancers, and play their roles through several signaling pathways. According to previous reports, expression of REG was mainly induced by various inflammatory cytokines and exogenous growth factors (13). However, there is little information on these pathways. Some studies have demonstrated that cytokines such as IFN-γ, IL-6, IL-22, and TNF-α, enhance the expression of REG I (46,49,56–58). In addition, it is revealed that IL-8 regulates the expression of REG protein in gastric cancer cells (59) and that REG I acts as an anti-apoptotic factor through the STAT3 signaling pathway by increasing the expression and phosphorylation of Akt and Bad in gastric cancer cells (60). Furthermore, some studies demonstrated that PPARγ activator of thiazolidinediones such as ciglitazone and troglitazone inhibited REG Iα gene transcription (61). However, the biological function and cell signaling pathway of REG III have not been elucidated.
In the present study, we investigated the stimulators for the induction of the expression of REG III in HNSCC in vitro. In comparison with other type of REG family genes, expression of REG III was not induced by inflammatory cytokines, growth factors, and PPARγ activator of thiazolidinediones. We first revealed that resveratrol, which is a naturally occurring polyphenol, significantly increased the REG III promoter activity and the mRNA levels of REG III in HNSCC cells.
Resveratrol is a natural compound present in fruits including red grapes, vegetables and beverages including wine that are part of the human diet (62–64). In recent years, many studies indicated that resveratrol is associated with antioxidant, anti-inflammatory, and anticarcinogenic effects (53,65,66). Concerning the anticarcinogenic potential of resveratrol, a number of studies have suggested that resveratrol modulates multiple cellular processes, including cell proliferation, apoptosis, inflammation, and angiogenesis (63,67–71). Several reports indicate that resveratrol inhibits proliferation of cancer cells by inhibiting cell cycle progression (72–75). Moreover, recent studies support the role of resveratrol in inhibition of cancer invasion (76,77). In the present study, we observed a reduction in cell growth rates and the enhancement of chemo- and radiosensitivity in HNSCC cells treated with resveratrol when compared with untreated cells as a control. Furthermore, the present study demonstrated that resveratrol blocked cancer invasion in HNSCC cells. These results were compatible to the anticarcinogenic effect in cells transfected with REG III (44). It can be presumed that resveratrol could enhance the chemo- and radiosensitivity and inhibit cancer progression through the REG III expression pathway in HNSCC cells. However, the downstream signaling pathway of REG III is still unresolved. The signaling pathway of how REG III reduces cell proliferation, blocks cancer invasion, and enhances the chemo- and radiosensitivity in HNSCC need to be investigated in future studies.
In summary, these data suggested that resveratrol can play an important role in the improvement of survival for HNSCC through the REG III expression pathway and can be a potential candidate for novel anticancer drugs for patients with HNSCC.
Acknowledgements
This study was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
References
|
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar | |
|
Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Argiris A, Karamouzis MV, Raben D and Ferris RL: Head and neck cancer. Lancet. 371:1695–1709. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Pignon JP, le Maître A, Maillard E and Bourhis J; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol. 92:4–14. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Ozer E, Grecula JC, Agrawal A, Rhoades CA, Young DC and Schuller DE: Long-term results of a multimodal intensification regimen for previously untreated advanced resectable squamous cell cancer of the oral cavity, oropharynx, or hypopharynx. Laryngoscope. 116:607–612. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Ang KK, Trotti A, Brown BW, Garden AS, Foote RL, Morrison WH, Geara FB, Klotch DW, Goepfert H and Peters LJ: Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 51:571–578. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Cooper JS, Zhang Q, Pajak TF, Forastiere AA, Jacobs J, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, et al: Long-term follow-up of the RTOG 9501/intergroup phase III trial: Postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 84:1198–1205. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Adelstein DJ, Saxton JP, Rybicki LA, Esclamado RM, Wood BG, Strome M, Lavertu P, Lorenz RR and Carroll MA: Multiagent concurrent chemoradiotherapy for locoregionally advanced squamous cell head and neck cancer: Mature results from a single institution. J Clin Oncol. 24:1064–1071. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Goldenberg D, Lee J, Koch WM, Kim MM, Trink B, Sidransky D and Moon CS: Habitual risk factors for head and neck cancer. Otolaryngol Head Neck Surg. 131:986–993. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Kumar B, Cordell KG, Lee JS, Worden FP, Prince ME, Tran HH, Wolf GT, Urba SG, Chepeha DB, Teknos TN, et al: EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J Clin Oncol. 26:3128–3137. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Worden FP, Kumar B, Lee JS, Wolf GT, Cordell KG, Taylor JM, Urba SG, Eisbruch A, Teknos TN, Chepeha DB, et al: Chemo-selection as a strategy for organ preservation in advanced oropharynx cancer: Response and survival positively associated with HPV16 copy number. J Clin Oncol. 26:3138–3146. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Shiboski CH, Schmidt BL and Jordan RC: Tongue and tonsil carcinoma: Increasing trends in the U.S. population ages 20–44 years. Cancer. 103:1843–1849. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Takasawa S: Regenerating gene (REG) product and its potential clinical usage. Expert Opin Ther Targets. 20:541–550. 2016. View Article : Google Scholar | |
|
Watanabe T, Yonekura H, Terazono K, Yamamoto H and Okamoto H: Complete nucleotide sequence of human reg gene and its expression in normal and tumoral tissues. The reg protein, pancreatic stone protein, and pancreatic thread protein are one and the same product of the gene. J Biol Chem. 265:7432–7439. 1990.PubMed/NCBI | |
|
Fukui H, Kinoshita Y, Maekawa T, Okada A, Waki S, Hassan S, Okamoto H and Chiba T: Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats. Gastroenterology. 115:1483–1493. 1998. View Article : Google Scholar : PubMed/NCBI | |
|
Higham AD, Bishop LA, Dimaline R, Blackmore CG, Dobbins AC, Varro A, Thompson DG and Dockray GJ: Mutations of RegIalpha are associated with enterochromaffin-like cell tumor development in patients with hypergastrinemia. Gastroenterology. 116:1310–1318. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Shinozaki S, Nakamura T, Iimura M, Kato Y, Iizuka B, Kobayashi M and Hayashi N: Upregulation of Reg 1α and GW112 in the epithelium of inflamed colonic mucosa. Gut. 48:623–629. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Ose T, Kadowaki Y, Fukuhara H, Kazumori H, Ishihara S, Udagawa J, Otani H, Takasawa S, Okamoto H and Kinoshita Y: Reg I-knockout mice reveal its role in regulation of cell growth that is required in generation and maintenance of the villous structure of small intestine. Oncogene. 26:349–359. 2007. View Article : Google Scholar | |
|
Zhang YW, Ding LS and Lai MD: Reg gene family and human diseases. World J Gastroenterol. 9:2635–2641. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Zhao J, Wang J, Wang H and Lai M: Reg proteins and their roles in inflammation and cancer of the human digestive system. Adv Clin Chem. 61:153–173. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Terazono K, Yamamoto H, Takasawa S, Shiga K, Yonemura Y, Tochino Y and Okamoto H: A novel gene activated in regenerating islets. J Biol Chem. 263:2111–2114. 1988.PubMed/NCBI | |
|
Moriizumi S, Watanabe T, Unno M, Nakagawara K, Suzuki Y, Miyashita H, Yonekura H and Okamoto H: Isolation, structural determination and expression of a novel reg gene, human regI β. Biochim Biophys Acta. 1217:199–202. 1994. View Article : Google Scholar : PubMed/NCBI | |
|
Sanchez D, Figarella C, Marchand-Pinatel S, Bruneau N and Guy-Crotte O: Preferential expression of reg I β gene in human adult pancreas. Biochem Biophys Res Commun. 284:729–737. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Hervieu V, Christa L, Gouysse G, Bouvier R, Chayvialle JA, Bréchot C and Scoazec JY: HIP/PAP, a member of the reg family, is expressed in glucagon-producing enteropancreatic endocrine cells and tumors. Hum Pathol. 37:1066–1075. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Drickamer K: Two distinct classes of carbohydrate-recognition domains in animal lectins. J Biol Chem. 263:9557–9560. 1988.PubMed/NCBI | |
|
Dusetti NJ, Frigerio JM, Fox MF, Swallow DM, Dagorn JC and Iovanna JL: Molecular cloning, genomic organization, and chromosomal localization of the human pancreatitis-associated protein (PAP) gene. Genomics. 19:108–114. 1994. View Article : Google Scholar : PubMed/NCBI | |
|
Lasserre C, Simon MT, Ishikawa H, Diriong S, Nguyen VC, Christa L, Vernier P and Brechot C: Structural organization and chromosomal localization of a human gene (HIP/PAP) encoding a C-type lectin overexpressed in primary liver cancer. Eur J Biochem. 224:29–38. 1994. View Article : Google Scholar : PubMed/NCBI | |
|
Nata K, Liu Y, Xu L, Ikeda T, Akiyama T, Noguchi N, Kawaguchi S, Yamauchi A, Takahashi I, Shervani NJ, et al: Molecular cloning, expression and chromosomal localization of a novel human REG family gene, REG III. Gene. 340:161–170. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Hartupee JC, Zhang H, Bonaldo MF, Soares MB and Dieckgraefe BK: Isolation and characterization of a cDNA encoding a novel member of the human regenerating protein family: Reg IV. Biochim Biophys Acta. 1518:287–293. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Watanabe T, Yonemura Y, Yonekura H, Suzuki Y, Miyashita H, Sugiyama K, Moriizumi S, Unno M, Tanaka O and Kondo H: Pancreatic beta-cell replication and amelioration of surgical diabetes by Reg protein. Proc Natl Acad Sci USA. 91:3589–3592. 1994. View Article : Google Scholar : PubMed/NCBI | |
|
Asahara M, Mushiake S, Shimada S, Fukui H, Kinoshita Y, Kawanami C, Watanabe T, Tanaka S, Ichikawa A, Uchiyama Y, et al: Reg gene expression is increased in rat gastric enterochromaffin-like cells following water immersion stress. Gastroenterology. 111:45–55. 1996. View Article : Google Scholar : PubMed/NCBI | |
|
Macadam RC, Sarela AI, Farmery SM, Robinson PA, Markham AF and Guillou PJ: Death from early colorectal cancer is predicted by the presence of transcripts of the REG gene family. Br J Cancer. 83:188–195. 2000.PubMed/NCBI | |
|
Violette S, Festor E, Pandrea-Vasile I, Mitchell V, Adida C, Dussaulx E, Lacorte JM, Chambaz J, Lacasa M and Lesuffleur T: Reg IV, a new member of the regenerating gene family, is overexpressed in colorectal carcinomas. Int J Cancer. 103:185–193. 2003. View Article : Google Scholar | |
|
Oue N, Mitani Y, Aung PP, Sakakura C, Takeshima Y, Kaneko M, Noguchi T, Nakayama H and Yasui W: Expression and localization of Reg IV in human neoplastic and non-neoplastic tissues: Reg IV expression is associated with intestinal and neuroendocrine differentiation in gastric adenocarcinoma. J Pathol. 207:185–198. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Yonemura Y, Sakurai S, Yamamoto H, Endou Y, Kawamura T, Bandou E, Elnemr A, Sugiyama K, Sasaki T, Akiyama T, et al: REG gene expression is associated with the infiltrating growth of gastric carcinoma. Cancer. 98:1394–1400. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Dhar DK, Udagawa J, Ishihara S, Otani H, Kinoshita Y, Takasawa S, Okamoto H, Kubota H, Fujii T, Tachibana M, et al: Expression of regenerating gene I in gastric adenocarcinomas: Correlation with tumor differentiation status and patient survival. Cancer. 100:1130–1136. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Bishnupuri KS, Luo Q, Murmu N, Houchen CW, Anant S and Dieckgraefe BK: Reg IV activates the epidermal growth factor receptor/Akt/AP-1 signaling pathway in colon adenocarcinomas. Gastroenterology. 130:137–149. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Hayashi K, Motoyama S, Koyota S, Koizumi Y, Wang J, Takasawa S, Itaya-Hironaka A, Sakuramoto-Tsuchida S, Maruyama K, Saito H, et al: REG I enhances chemo- and radiosensitivity in squamous cell esophageal cancer cells. Cancer Sci. 99:2491–2495. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou L, Zhang R, Wang L, Shen S, Okamoto H, Sugawara A, Xia L, Wang X, Noguchi N, Yoshikawa T, et al: Upregulation of REG Ialpha accelerates tumor progression in pancreatic cancer with diabetes. Int J Cancer. 127:1795–1803. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Fukui H, Fujii S, Takeda J, Kayahara T, Sekikawa A, Nanakin A, Suzuki K, Hisatsune H, Seno H, Sawada M, et al: Expression of reg I α protein in human gastric cancers. Digestion. 69:177–184. 2004. View Article : Google Scholar | |
|
Minamiya Y, Kawai H, Saito H, Ito M, Hosono Y, Motoyama S, Katayose Y, Takahashi N and Ogawa J: REG1A expression is an independent factor predictive of poor prognosis in patients with non-small cell lung cancer. Lung Cancer. 60:98–104. 2008. View Article : Google Scholar | |
|
Mauro V, Carette D, Chevallier D, Michiels JF, Segretain D, Pointis G and Sénégas-Balas F: Reg I protein in healthy and seminoma human testis. Histol Histopathol. 23:1195–1203. 2008.PubMed/NCBI | |
|
Kimura M, Naito H, Tojo T, Itaya-Hironaka A, Dohi Y, Yoshimura M, Nakagawara K, Takasawa S and Taniguchi S: REG Iα gene expression is linked with the poor prognosis of lung adenocarcinoma and squamous cell carcinoma patients via discrete mechanisms. Oncol Rep. 30:2625–2631. 2013.PubMed/NCBI | |
|
Masui T, Ota I, Itaya-Hironaka A, Takeda M, Kasai T, Yamauchi A, Sakuramoto-Tsuchida S, Mikami S, Yane K, Takasawa S, et al: Expression of REG III and prognosis in head and neck cancer. Oncol Rep. 30:573–578. 2013.PubMed/NCBI | |
|
Ota H, Tamaki S, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Morioka T, Takasawa S and Kimura H: Attenuation of glucose-induced insulin secretion by intermittent hypoxia via down-regulation of CD38. Life Sci. 90:206–211. 2012. View Article : Google Scholar | |
|
Akiyama T, Takasawa S, Nata K, Kobayashi S, Abe M, Shervani NJ, Ikeda T, Nakagawa K, Unno M, Matsuno S, et al: Activation of Reg gene, a gene for insulin-producing β-cell regeneration: Poly(ADP-ribose) polymerase binds Reg promoter and regulates the transcription by autopoly(ADP-ribosyl)ation. Proc Natl Acad Sci USA. 98:48–53. 2001. | |
|
Nakagawa K, Takasawa S, Nata K, Yamauchi A, Itaya-Hironaka A, Ota H, Yoshimoto K, Sakuramoto-Tsuchida S, Miyaoka T, Takeda M, et al: Prevention of Reg I-induced β-cell apoptosis by IL-6/dexamethasone through activation of HGF gene regulation. Biochim Biophys Acta. 1833:2988–2995. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Yamauchi A, Itaya-Hironaka A, Sakuramoto-Tsuchida S, Takeda M, Yoshimoto K, Miyaoka T, Fujimura T, Tsujinaka H, Tsuchida C, Ota H, et al: Synergistic activations of REG Iα and REG Iβ promoters by IL-6 and glucocorticoids through JAK/STAT pathway in human pancreatic β cells. J Diabetes Res. 2015:1730582015. View Article : Google Scholar | |
|
Fujimura T, Fujimoto T, Itaya-Hironaka A, Miyaoka T, Yoshimoto K, Yamauchi A, Sakuramoto-Tsuchida S, Kondo S, Takeda M, Tsujinaka H, et al: Interleukin-6/STAT pathway is responsible for the induction of gene expression of REG Iα, a new auto-antigen in Sjögren’s syndrome patients, in salivary duct epithelial cells. Biochem Biophys Rep. 2:69–74. 2015. | |
|
Tsujinaka H, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Ota H, Takeda M, Fujimura T, Takasawa S and Ogata N: Human retinal pigment epithelial cell proliferation by the combined stimulation of hydroquinone and advanced glycation end-products via up-regulation of VEGF gene. Biochem Biophys Rep. 2:123–131. 2015. | |
|
Takasawa S, Kuroki M, Nata K, Noguchi N, Ikeda T, Yamauchi A, Ota H, Itaya-Hironaka A, Sakuramoto-Tsuchida S, Takahashi I, et al: A novel ryanodine receptor expressed in pancreatic islets by alternative splicing from type 2 ryanodine receptor gene. Biochem Biophys Res Commun. 397:140–145. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Ota H, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Miyaoka T, Fujimura T, Tsujinaka H, Yoshimoto K, Nakagawara K, Tamaki S, et al: Pancreatic β cell proliferation by intermittent hypoxia via up-regulation of Reg family genes and HGF gene. Life Sci. 93:664–672. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Liu XJ, Bao HR, Zeng XL and Wei JM: Effects of resveratrol and genistein on nuclear factor κB, tumor necrosis factor α and matrix metalloproteinase 9 in patients with chronic obstructive pulmonary disease. Mol Med Rep. 13:4266–4272. 2016.PubMed/NCBI | |
|
Ogawa H, Fukushima K, Naito H, Funayama Y, Unno M, Takahashi K, Kitayama T, Matsuno S, Ohtani H, Takasawa S, et al: Increased expression of HIP/PAP and regenerating gene III in human inflammatory bowel disease and a murine bacterial reconstitution model. Inflamm Bowel Dis. 9:162–170. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Vives-Pi M, Takasawa S, Pujol-Autonell I, Planas R, Cabre E, Ojanguren I, Montraveta M, Santos AL and Ruiz-Ortiz E: Biomarkers for diagnosis and monitoring of celiac disease. J Clin Gastroenterol. 47:308–313. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Dusetti NJ, Mallo GV, Ortiz EM, Keim V, Dagorn JC and Iovanna JL: Induction of lithostathine/reg mRNA expression by serum from rats with acute pancreatitis and cytokines in pancreatic acinar AR-42J cells. Arch Biochem Biophys. 330:129–132. 1996. View Article : Google Scholar : PubMed/NCBI | |
|
Kinoshita Y, Ishihara S, Kadowaki Y, Fukui H and Chiba T: Reg protein is a unique growth factor of gastric mucosal cells. J Gastroenterol. 39:507–513. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Usami S, Motoyama S, Koyota S, Wang J, Hayashi-Shibuya K, Maruyama K, Takahashi N, Saito H, Minamiya Y, Takasawa S, et al: Regenerating gene I regulates interleukin-6 production in squamous esophageal cancer cells. Biochem Biophys Res Commun. 392:4–8. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Yoshino N, Ishihara S, Rumi MA, Ortega-Cava CF, Yuki T, Kazumori H, Takazawa S, Okamoto H, Kadowaki Y and Kinoshita Y: Interleukin-8 regulates expression of Reg protein in Helicobacter pylori-infected gastric mucosa. Am J Gastroenterol. 100:2157–2166. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Sekikawa A, Fukui H, Fujii S, Ichikawa K, Tomita S, Imura J, Chiba T and Fujimori T: REG Ialpha protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells. Carcinogenesis. 29:76–83. 2008. View Article : Google Scholar | |
|
Yamauchi A, Takahashi I, Takasawa S, Nata K, Noguchi N, Ikeda T, Yoshikawa T, Shervani NJ, Suzuki I, Uruno A, et al: Thiazolidinediones inhibit REG Iα gene transcription in gastrointestinal cancer cells. Biochem Biophys Res Commun. 379:743–748. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Cal C, Garban H, Jazirehi A, Yeh C, Mizutani Y and Bonavida B: Resveratrol and cancer: Chemoprevention, apoptosis, and chemo-immunosensitizing activities. Curr Med Chem Anticancer Agents. 3:77–93. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Rubiolo JA, López-Alonso H, Martín-Vázquez V, Fol-Rodríguéz NM, Vieytes MR, Botana LM and Vega FV: Resveratrol inhibits proliferation of primary rat hepatocytes in G0/G1 by inhibiting DNA synthesis. Folia Biol (Praha). 58:166–172. 2012. | |
|
Frémont L: Biological effects of resveratrol. Life Sci. 66:663–673. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Kundu JK and Surh YJ: Cancer chemopreventive and therapeutic potential of resveratrol: Mechanistic perspectives. Cancer Lett. 269:243–261. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Kovacic P and Somanathan R: Multifaceted approach to resveratrol bioactivity: Focus on antioxidant action, cell signaling and safety. Oxid Med Cell Longev. 3:86–100. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Estrov Z, Shishodia S, Faderl S, Harris D, Van Q, Kantarjian HM, Talpaz M and Aggarwal BB: Resveratrol blocks interleukin-1β-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells. Blood. 102:987–995. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Liang YC, Tsai SH, Chen L, Lin-Shiau SY and Lin JK: Resveratrol-induced G2 arrest through the inhibition of CDK7 and p34CDC2 kinases in colon carcinoma HT29 cells. Biochem Pharmacol. 65:1053–1060. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
ElAttar TM and Virji AS: Modulating effect of resveratrol and quercetin on oral cancer cell growth and proliferation. Anticancer Drugs. 10:187–193. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Yeh CB, Hsieh MJ, Lin CW, Chiou HL, Lin PY, Chen TY and Yang SF: The antimetastatic effects of resveratrol on hepatocellular carcinoma through the downregulation of a metastasis-associated protease by SP-1 modulation. PLoS One. 8:e566612013. View Article : Google Scholar : PubMed/NCBI | |
|
Shankar S, Singh G and Srivastava RK: Chemoprevention by resveratrol: Molecular mechanisms and therapeutic potential. Front Biosci. 12:4839–4854. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Hong YB, Kang HJ, Kim HJ, Rosen EM, Dakshanamurthy S, Rondanin R, Baruchello R, Grisolia G, Daniele S and Bae I: Inhibition of cell proliferation by a resveratrol analog in human pancreatic and breast cancer cells. Exp Mol Med. 41:151–160. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Liu B, Zhou Z, Zhou W, Liu J, Zhang Q, Xia J, Liu J, Chen N, Li M and Zhu R: Resveratrol inhibits proliferation in human colorectal carcinoma cells by inducing G1/S phase cell cycle arrest and apoptosis through caspase/cyclin CDK pathways. Mol Med Rep. 10:1697–1702. 2014.PubMed/NCBI | |
|
Wang G, Guo X, Chen H, Lin T, Xu Y, Chen Q, Liu J, Zeng J, Zhang XK and Yao X: A resveratrol analog, phoyunbene B, induces G2/M cell cycle arrest and apoptosis in HepG2 liver cancer cells. Bioorg Med Chem Lett. 22:2114–2118. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Bai Y, Mao QQ, Qin J, Zheng XY, Wang YB, Yang K, Shen HF and Xie LP: Resveratrol induces apoptosis and cell cycle arrest of human T24 bladder cancer cells in vitro and inhibits tumor growth in vivo. Cancer Sci. 101:488–493. 2010. View Article : Google Scholar | |
|
Baribeau S, Chaudhry P, Parent S and Asselin É: Resveratrol inhibits cisplatin-induced epithelial-to-mesenchymal transition in ovarian cancer cell lines. PLoS One. 9:e869872014. View Article : Google Scholar : PubMed/NCBI | |
|
Lin FY, Hsieh YH, Yang SF, Chen CT, Tang CH, Chou MY, Chuang YT, Lin CW and Chen MK: Resveratrol suppresses TPA-induced matrix metalloproteinase-9 expression through the inhibition of MAPK pathways in oral cancer cells. J Oral Pathol Med. 44:699–706. 2015. View Article : Google Scholar |
