PGD2/PTGDR2 Signal Affects the Viability, Invasion, Apoptosis, and Stemness of Gastric Cancer Stem Cells and Prevents the Progression of Gastric Cancer


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Толық мәтін

Аннотация

Background:Prostaglandin D2 (PGD2) has been shown to restrict the occurrence and development of multiple cancers; nevertheless, its underlying molecular mechanism has not been fully elucidated. The present study investigated the effect of PGD2 on the biological function of the enriched gastric cancer stem cells (GCSCs), as well as its underlying molecular mechanism, to provide a theoretical basis and potential therapeutic drugs for gastric cancer (GC) treatment.

Methods:The plasma PGD2 levels were detected by Enzyme-linked immunosorbent assay (ELISA). Silencing of lipocalin prostaglandin D synthetases (L-PTGDS) and prostaglandin D2 receptor 2 (PTGDR2) was carried out in GCSCs from SGC-7901 and HGC-27 cell lines. Cell Counting Kit-8, transwell, flow cytometry, and western blotting assays were used to determine cell viability, invasion, apoptosis, and stemness of GCSCs. In vivo xenograft models were used to assess tumor growth.

Results:Clinically, it was found that the plasma PGD2 level decreased significantly in patients with GC. PGD2 suppressed viability, invasion, and stemness and increased the apoptosis of GCSCs. Downregulating L-PTGDS and PTGDR2 promoted viability, invasion, and stemness and reduced the apoptosis of GCSCs. Moreover, the inhibition of GCSCs induced by PGD2 was eliminated by downregulating the expression of PTGDR2. The results of in vivo experiments were consistent with those of in vitro experiments.

Conclusion:Our data suggest that PGD2 may be an important marker and potential therapeutic target in the clinical management of GC. L-PTGDS/PTGDR2 may be one of the critical targets for GC therapy. The PGD2/PTGDR2 signal affects the viability, invasion, apoptosis, and stemness of GCSCs and prevents the progression of GC.

Авторлар туралы

Qiang Zhang

Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College

Хат алмасуға жауапты Автор.
Email: info@benthamscience.net

Feifan Wang

Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College

Email: info@benthamscience.net

Yan Huang

Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College

Email: info@benthamscience.net

Peiyao Gao

Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College

Email: info@benthamscience.net

Na Wang

Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College

Email: info@benthamscience.net

Hengjin Tian

Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College

Email: info@benthamscience.net

Amin Chen

Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College

Email: info@benthamscience.net

Yuyun Li

School of Laboratory Medicine, Bengbu Medical College

Хат алмасуға жауапты Автор.
Email: info@benthamscience.net

Fengchao Wang

Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College

Хат алмасуға жауапты Автор.
Email: info@benthamscience.net

Әдебиет тізімі

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249. doi: 10.3322/caac.21660 PMID: 33538338
  2. Thrift, A.P.; El-Serag, H.B. Burden of gastric cancer. Clin. Gastroenterol. Hepatol., 2020, 18(3), 534-542. doi: 10.1016/j.cgh.2019.07.045 PMID: 31362118
  3. Xu, G.; Shen, J.; Ou Yang, X.; Sasahara, M.; Su, X. Cancer stem cells: The ‘heartbeat’ of gastric cancer. J. Gastroenterol., 2013, 48(7), 781-797. doi: 10.1007/s00535-012-0712-y PMID: 23184096
  4. Nio, K.; Yamashita, T.; Kaneko, S. The evolving concept of liver cancer stem cells. Mol. Cancer, 2017, 16(1), 4. doi: 10.1186/s12943-016-0572-9 PMID: 28137313
  5. Luo, S.; Li, Y.; Ma, R.; Liu, J.; Xu, P.; Zhang, H.; Tang, K.; Ma, J.; Liu, N.; Zhang, Y.; Sun, Y.; Ji, T.; Liang, X.; Yin, X.; Liu, Y.; Tong, W.; Niu, Y.; Wang, N.; Wang, X.; Huang, B. Downregulation of PCK2 remodels tricarboxylic acid cycle in tumor-repopulating cells of melanoma. Oncogene, 2017, 36(25), 3609-3617. doi: 10.1038/onc.2016.520 PMID: 28166201
  6. Wicha, M.S. Cancer stem cells and metastasis: Lethal seeds. Clin. Cancer Res., 2006, 12(19), 5606-5607. doi: 10.1158/1078-0432.CCR-06-1537 PMID: 17020960
  7. Abbaszadegan, M.R.; Bagheri, V.; Razavi, M.S.; Momtazi, A.A.; Sahebkar, A.; Gholamin, M. Isolation, identification, and characterization of cancer stem cells: A review. J. Cell. Physiol., 2017, 232(8), 2008-2018. doi: 10.1002/jcp.25759 PMID: 28019667
  8. Hu, X.; Cong, Y.; Luo, H.H.; Wu, S.; Zhao, L.E.; Liu, Q.; Yang, Y. Cancer stem cells therapeutic target database: The first comprehensive database for therapeutic targets of cancer stem cells. Stem Cells Transl. Med., 2017, 6(2), 331-334. doi: 10.5966/sctm.2015-0289 PMID: 28191780
  9. Barker, N.; Huch, M.; Kujala, P.; van de Wetering, M.; Snippert, H.J.; van Es, J.H.; Sato, T.; Stange, D.E.; Begthel, H.; van den Born, M.; Danenberg, E.; van den Brink, S.; Korving, J.; Abo, A.; Peters, P.J.; Wright, N.; Poulsom, R.; Clevers, H. Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell, 2010, 6(1), 25-36. doi: 10.1016/j.stem.2009.11.013 PMID: 20085740
  10. Zong, L.; Abe, M.; Seto, Y.; Ji, J. The challenge of screening for early gastric cancer in China. Lancet, 2016, 388(10060), 2606. doi: 10.1016/S0140-6736(16)32226-7 PMID: 27894662
  11. Mani, S.A.; Guo, W.; Liao, M.J.; Eaton, E.N.; Ayyanan, A.; Zhou, A.Y.; Brooks, M.; Reinhard, F.; Zhang, C.C.; Shipitsin, M.; Campbell, L.L.; Polyak, K.; Brisken, C.; Yang, J.; Weinberg, R.A. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 2008, 133(4), 704-715. doi: 10.1016/j.cell.2008.03.027 PMID: 18485877
  12. Wang, B.; Chen, Q.; Cao, Y.; Ma, X.; Yin, C.; Jia, Y.; Zang, A.; Fan, W. LGR5 is a gastric cancer stem cell marker associated with stemness and the EMT signature genes NANOG, NANOGP8, PRRX1, TWIST1, and BMI1. PLoS One, 2016, 11(12), e0168904. doi: 10.1371/journal.pone.0168904 PMID: 28033430
  13. Zhang, L.; Xu, Z.; Xu, X.; Zhang, B.; Wu, H.; Wang, M.; Zhang, X.; Yang, T.; Cai, J.; Yan, Y.; Mao, F.; Zhu, W.; Shao, Q.; Qian, H.; Xu, W. SALL4, a novel marker for human gastric carcinogenesis and metastasis. Oncogene, 2014, 33(48), 5491-5500. doi: 10.1038/onc.2013.495 PMID: 24276240
  14. Li, X.B.; Yang, G.; Zhu, L.; Tang, Y.L.; Zhang, C.; Ju, Z.; Yang, X.; Teng, Y. Gastric Lgr5+ stem cells are the cellular origin of invasive intestinal-type gastric cancer in mice. Cell Res., 2016, 26(7), 838-849. doi: 10.1038/cr.2016.47 PMID: 27091432
  15. Thapa, R.; Wilson, G.D. The importance of CD44 as a stem cell biomarker and therapeutic target in cancer. Stem Cells Int., 2016, 2016, 1-15. doi: 10.1155/2016/2087204 PMID: 27200096
  16. Rajakariar, R.; Hilliard, M.; Lawrence, T.; Trivedi, S.; Colville-Nash, P.; Bellingan, G.; Fitzgerald, D.; Yaqoob, M.M.; Gilroy, D.W. Hematopoietic prostaglandin D 2 synthase controls the onset and resolution of acute inflammation through PGD 2 and 15-deoxyΔ 12–14 PGJ 2. Proc. Natl. Acad. Sci., 2007, 104(52), 20979-20984. doi: 10.1073/pnas.0707394104 PMID: 18077391
  17. Säfholm, J.; Abma, W.; Liu, J.; Balgoma, D.; Fauland, A.; Kolmert, J.; Wheelock, C.E.; Adner, M.; Dahlén, S.E. Prostaglandin D2 inhibits mediator release and antigen induced bronchoconstriction in the Guinea pig trachea by activation of DP1 receptors. Eur. J. Pharmacol., 2021, 907, 174282. doi: 10.1016/j.ejphar.2021.174282 PMID: 34175307
  18. Scheaffer, H.L.; Borazjani, A.; Szafran, B.N.; Ross, M.K. Inactivation of CES1 blocks prostaglandin D 2 glyceryl ester catabolism in monocytes/macrophages and enhances its anti-inflammatory effects, whereas the pro-inflammatory effects of prostaglandin E 2 glyceryl ester are attenuated. ACS Omega, 2020, 5(45), 29177-29188. doi: 10.1021/acsomega.0c03961 PMID: 33225149
  19. Suzuki, K.; Suzuki, S.; Ishii, Y.; Okamura, M.; Matsubara, T.; Fujita, H.; Nozawa, N.; Kobayashi, S.; Hirata, K. Plasma prostaglandin D2 synthase levels in sleep and neurological diseases. J. Neurol. Sci., 2020, 411, 116692. doi: 10.1016/j.jns.2020.116692 PMID: 31981928
  20. Wu, S.; Tang, S.; Peng, H.; Jiang, Y.; Liu, Y.; Wu, Z.; Liu, Q.; Zhu, X. Effects of lentivirus-mediated CCR3 RNA interference on the function of mast cells of allergic rhinitis in mice. Int. Immunopharmacol., 2020, 78, 106011. doi: 10.1016/j.intimp.2019.106011 PMID: 31776094
  21. Murata, T.; Aritake, K.; Matsumoto, S.; Kamauchi, S.; Nakagawa, T.; Hori, M.; Momotani, E.; Urade, Y.; Ozaki, H. Prostagladin D 2 is a mast cell-derived antiangiogenic factor in lung carcinoma. Proc. Natl. Acad. Sci., 2011, 108(49), 19802-19807. doi: 10.1073/pnas.1110011108 PMID: 22106279
  22. Shimakura, S.; Boland, C.R. Eicosanoid production by the human gastric cancer cell line AGS and its relation to cell growth. Cancer Res., 1992, 52(7), 1744-1749. PMID: 1551103
  23. Kim, J.; Yang, P.; Suraokar, M.; Sabichi, A.L.; Llansa, N.D.; Mendoza, G.; Subbarayan, V.; Logothetis, C.J.; Newman, R.A.; Lippman, S.M.; Menter, D.G. Suppression of prostate tumor cell growth by stromal cell prostaglandin D synthase-derived products. Cancer Res., 2005, 65(14), 6189-6198. doi: 10.1158/0008-5472.CAN-04-4439 PMID: 16024620
  24. Fukuoka, T.; Yashiro, M.; Kinoshita, H.; Morisaki, T.; Hasegawa, T.; Hirakawa, T.; Aomatsu, N.; Takeda, H.; Maruyama, T.; Hirakawa, K. Prostaglandin D synthase is a potential novel therapeutic agent for the treatment of gastric carcinomas expressing PPARγ. Int. J. Cancer, 2015, 137(5), 1235-1244. doi: 10.1002/ijc.29392 PMID: 25516376
  25. Nakamura, M.; Tsumura, H.; Satoh, T.; Matsumoto, K.; Maruyama, H.; Majima, M.; Kitasato, H. Tumor apoptosis in prostate cancer by PGD2 and its metabolite 15d-PGJ2 in murine model. Biomed. Pharmacother., 2013, 67(1), 66-71. doi: 10.1016/j.biopha.2012.10.012 PMID: 23206752
  26. Zhang, B.; Bie, Q.; Wu, P.; Zhang, J.; You, B.; Shi, H.; Qian, H.; Xu, W. PGD2/PTGDR2 signaling restricts the self-renewal and tumorigenesis of gastric cancer. Stem Cells, 2018, 36(7), 990-1003. doi: 10.1002/stem.2821 PMID: 29604141
  27. Iwanaga, K.; Nakamura, T.; Maeda, S.; Aritake, K.; Hori, M.; Urade, Y.; Ozaki, H.; Murata, T. Mast cell-derived prostaglandin D2 inhibits colitis and colitis-associated colon cancer in mice. Cancer Res., 2014, 74(11), 3011-3019. doi: 10.1158/0008-5472.CAN-13-2792 PMID: 24879565
  28. Hu, S.; Zhang, J.; Fang, X.; Guo, G.; Dai, J.; Sheng, Z.; Li, D.; Chen, J.; Zhang, L.; Liu, C.; Gao, Y. Identification of microRNA hsa-miR-30c-5p as an inhibitory factor in the progression of hepatocellular carcinoma and investigation of its regulatory network via comprehensive analysis. Bioengineered, 2021, 12(1), 7154-7166. doi: 10.1080/21655979.2021.1979439 PMID: 34503377
  29. Wu, L.; Yu, K.; Chen, K.; Zhu, X.; Yang, Z.; Wang, Q.; Gao, J.; Wang, Y.; Cao, T.; Xu, H.; Pan, X.; Wang, L.; Xia, J.; Li, Y.; Wang, Z.P.; Ma, J. Fbxo45 facilitates pancreatic carcinoma progression by targeting USP49 for ubiquitination and degradation. Cell Death Dis., 2022, 13(3), 231. doi: 10.1038/s41419-022-04675-2 PMID: 35279684
  30. Ma, J.; Cui, Y.; Cao, T.; Xu, H.; Shi, Y.; Xia, J.; Tao, Y.; Wang, Z.P. PDS5B regulates cell proliferation and motility via upregulation of Ptch2 in pancreatic cancer cells. Cancer Lett., 2019, 460, 65-74. doi: 10.1016/j.canlet.2019.06.014 PMID: 31233836
  31. Ma, J.; Cao, T.; Cui, Y.; Zhang, F.; Shi, Y.; Xia, J.; Wang, Z.P. miR-223 regulates cell proliferation and invasion via targeting PDS5B in pancreatic cancer cells. Mol. Ther. Nucleic Acids, 2019, 14, 583-592. doi: 10.1016/j.omtn.2019.01.009 PMID: 30776580
  32. Biddle, A.; Mackenzie, I.C. Cancer stem cells and EMT in carcinoma. Cancer Metastasis Rev., 2012, 31(1-2), 285-293. doi: 10.1007/s10555-012-9345-0 PMID: 22302111
  33. Sun, J.; Sun, B.; Zhu, D.; Zhao, X.; Zhang, Y.; Dong, X.; Che, N.; Li, J.; Liu, F.; Zhao, N.; Zhang, D.; Liu, T.; Lin, X. HMGA2 regulates CD44 expression to promote gastric cancer cell motility and sphere formation. Am. J. Cancer Res., 2017, 7(2), 260-274. PMID: 28337375
  34. Ponti, D.; Costa, A.; Zaffaroni, N.; Pratesi, G.; Petrangolini, G.; Coradini, D.; Pilotti, S.; Pierotti, M.A.; Daidone, M.G. Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res., 2005, 65(13), 5506-5511. doi: 10.1158/0008-5472.CAN-05-0626 PMID: 15994920
  35. Alves, M.; Do Amaral, N.; Marchi, F.; Silva, F.; Da Costa, A.; Carvalho, K.; Baiocchi, G.; Soares, F.; De Brot, L.; Rocha, R. Prostaglandin D2 expression is prognostic in high‑grade serous ovarian cancer. Oncol. Rep., 2019, 41(4), 2254-2264. doi: 10.3892/or.2019.6984 PMID: 30720106
  36. Hall, J.A.; Rusten, M.; Abughazaleh, R.D.; Wuertz, B.; Souksavong, V.; Escher, P.; Ondrey, F. Effects of PPAR ‐γ agonists on oral cancer cell lines: Potential horizons for chemopreventives and adjunctive therapies. Head Neck, 2020, 42(9), 2542-2554. doi: 10.1002/hed.26286 PMID: 32519370
  37. DelGiorno, K.E.; Chung, C.Y.; Vavinskaya, V.; Maurer, H.C.; Novak, S.W.; Lytle, N.K.; Ma, Z.; Giraddi, R.R.; Wang, D.; Fang, L.; Naeem, R.F.; Andrade, L.R.; Ali, W.H.; Tseng, H.; Tsui, C.; Gubbala, V.B.; Ridinger-Saison, M.; Ohmoto, M.; Erikson, G.A.; O’Connor, C.; Shokhirev, M.N.; Hah, N.; Urade, Y.; Matsumoto, I.; Kaech, S.M.; Singh, P.K.; Manor, U.; Olive, K.P.; Wahl, G.M. Tuft cells inhibit pancreatic tumorigenesis in mice by producing prostaglandin D2. Gastroenterology, 2020, 159(5), 1866-1881.e8. doi: 10.1053/j.gastro.2020.07.037 PMID: 32717220
  38. Ferreira, M.T.; Gomes, R.N.; Panagopoulos, A.T.; de Almeida, F.G.; Veiga, J.C.E.; Colquhoun, A. Opposing roles of PGD2 in GBM. Prostaglandins Other Lipid Mediat., 2018, 134, 66-76. doi: 10.1016/j.prostaglandins.2017.10.002 PMID: 29042181
  39. Wu, L.; Lin, Q.; Ma, Z.; Chowdhury, F.A.; Mazumder, M.H.H.; Du, W. Mesenchymal PGD2 activates an ILC2-Treg axis to promote proliferation of normal and malignant HSPCs. Leukemia, 2020, 34(11), 3028-3041. doi: 10.1038/s41375-020-0843-8 PMID: 32366935
  40. Lin, Y.; Cheng, J.; Huang, X. The role of prostaglandin D2 in the mice model of ulcerative colitis associated carcinogenesis. Chin. J. Gastroenterol. Hepatol., 2020, 29, 992-997.
  41. Lu, Y.C.; Shi, J.Q.; Zhang, Z.X.; Zhou, J.Y.; Zhou, H.K.; Feng, Y.C.; Lu, Z.H.; Yang, S.Y.; Zhang, X.Y.; Liu, Y.; Li, Z.C.; Sun, Y.J.; Zheng, L.H.; Jiang, D.B.; Yang, K. Transcriptome based system biology exploration reveals homogeneous tumorigenicity of alimentary tract malignancy. Front. Oncol., 2021, 10, 580276. doi: 10.3389/fonc.2020.580276 PMID: 33552958
  42. Misawa, K.; Mima, M.; Satoshi, Y.; Imai, A.; Mochizuki, D.; Ishikawa, R.; Kita, J.; Yamaguchi, Y.; Endo, S.; Misawa, Y.; Mineta, H. Prostanoid receptor genes confer poor prognosis in head and neck squamous cell carcinoma via epigenetic inactivation. J. Transl. Med., 2020, 18(1), 31. doi: 10.1186/s12967-020-02214-1 PMID: 31969157
  43. Montgomery, T.A.; Xu, L.; Mason, S.; Chinnadurai, A.; Lee, C.G.; Elias, J.A.; Cantley, L.G. Breast regression protein–39/Chitinase 3–Like 1 promotes renal fibrosis after kidney injury via activation of myofibroblasts. J. Am. Soc. Nephrol., 2017, 28(11), 3218-3226. doi: 10.1681/ASN.2017010110 PMID: 28679671
  44. Su, Y.; Tian, X.; Gao, R.; Guo, W.; Chen, C.; Chen, C.; Jia, D.; Li, H.; Lv, X. Colon cancer diagnosis and staging classification based on machine learning and bioinformatics analysis. Comput. Biol. Med., 2022, 145, 105409. doi: 10.1016/j.compbiomed.2022.105409 PMID: 35339846
  45. Misawa, K.; Imai, A.; Kanazawa, T.; Mima, M.; Yamada, S.; Mochizuki, D.; Yamada, T.; Shinmura, D.; Ishikawa, R.; Kita, J.; Yamaguchi, Y.; Misawa, Y.; Mineta, H. G protein-coupled receptor genes, PTGDR1, PTGDR2, and PTGIR, are candidate epigenetic biomarkers and predictors for treated patients with HPV-associated oropharyngeal cancer. Microorganisms, 2020, 8(10), 1504. doi: 10.3390/microorganisms8101504 PMID: 33003642
  46. Lv, J.; Li, L. Hub genes and key pathway identification in colorectal cancer based on bioinformatic analysis. BioMed Res. Int., 2019, 2019, 1-13. doi: 10.1155/2019/1545680 PMID: 31781593
  47. He, L.P.; Chen, Y.F.; Yang, J. Investigation on the role and mechanism of prostagland in D2 synthase in non-small cell lung cancer. Zhonghua Yi Xue Za Zhi, 2017, 97(38), 3022-3027. doi: 10.3760/cma.j.issn.0376-2491.2017.38.016 PMID: 29061012
  48. Bie, Q.; Li, X.; Liu, S.; Yang, X.; Qian, Z.; Zhao, R.; Zhang, X.; Zhang, B. YAP promotes self-renewal of gastric cancer cells by inhibiting expression of L-PTGDS and PTGDR2. Int. J. Clin. Oncol., 2020, 25(12), 2055-2065. doi: 10.1007/s10147-020-01771-1 PMID: 32851567
  49. de Sousa e Melo. F.; Kurtova, A.V.; Harnoss, J.M.; Kljavin, N.; Hoeck, J.D.; Hung, J.; Anderson, J.E.; Storm, E.E.; Modrusan, Z.; Koeppen, H.; Dijkgraaf, G.J.P.; Piskol, R.; de Sauvage, F.J. A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. Nature, 2017, 543(7647), 676-680. doi: 10.1038/nature21713 PMID: 28358093

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