Tumor Biology

, Volume 37, Issue 12, pp 16317–16335 | Cite as

Integrated analysis identified an intestinal-like and a diffuse-like gene sets that predict gastric cancer outcome

  • Cheng Zhang
  • Li Min
  • Jiafei Liu
  • Wei Tian
  • Yong Han
  • Like Qu
  • Chengchao Shou
Original Article


The two major histological types of gastric cancer, intestinal and diffuse subtypes, have distinct epidemiological and pathophysiological features and were also suggested to be of diverse clinical outcomes. Although the gene expression spectrum of gastric cancer subtypes has been reported by previous studies, its linkage with gastric cancer clinical features and outcomes remains elusive. We investigated large-sample online gastric cancer datasets for seeking genes correlated with the clinical diversities between gastric cancer intestinal and diffuse subtypes. Genes differently expressed between the two subtypes were assessed by multiple statistical analysis and were testified on cellular level by quantitative RT-PCR. Related genes were combined to generate a risk signature, and their mutual linkages were also explored. Among genes overexpressed in intestinal subtype, ATPIF1, PRDX2, PRKAR2A, and SMC1A were correlated with positive prognosis. Among genes overexpressed in diffuse subtype, DTNA, GPR161, IDS, RHOQ, and TSHZ2 were correlated with negative prognosis. These nine genes were all novel independent prognostic factors. When used in combination as signatures, these two gene sets displayed strong efficacy for prediction of the prognosis and clinical variables in gastric and colorectal cancer. Hence, these two genes sets were respectively defined as the favorable intestinal-like and adverse diffuse-like gene sets. We identified nine novel genes correlated with the clinical diversity between the intestinal and diffuse subtypes of gastric cancer. The malignant changes from the intestinal to diffuse subtype might be due to the reduction of the four intestinal-like genes, as well as the elevation of the five diffuse-like genes.


Gastric cancer Lauren classification Subtype-related genes Prognostic markers Risk signatures 



We deeply appreciate Jing Yan for the kind provision of specimens and helpful suggestions on experimental design. This study was supported by the National 973 Program of China (2015CB553906).

Compliance with ethical standards

The experiments described in the manuscript comply with the current laws of the countries in which they were performed.

Conflict of interest


Supplementary material

13277_2016_5454_MOESM1_ESM.docx (19 kb)
Table S1 Comparison of the expression values of 4 intestinal- and 5 diffuse-like genes in all three gastric cancer datasets (student’s t test, p < 0.05 was considered significant). (DOCX 19 kb)
13277_2016_5454_MOESM2_ESM.docx (13 kb)
Table S2 Primer sequences for quantitative real-time PCR (DOCX 12 kb)
13277_2016_5454_Fig7_ESM.jpg (112 kb)
Fig. S1

Subtype-related genes’ relationship with gastric cancer patient survival and disease-free survival were assessed by ROC analysis. Predictive values of intestinal-like genes during follow-up in training and validating datasets were shown as (a and c), while predictive values of diffuse-like genes during follow-up in training and validating datasets were shown as (b and d) (SPSS 17.0). AUC area under curve (JPEG 112 kb)

13277_2016_5454_MOESM3_ESM.tif (2.1 mb)
High Resolution (TIFF 2144 kb)


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7–30. doi: 10.3322/caac.21332.CrossRefPubMedGoogle Scholar
  2. 2.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi: 10.3322/caac.20107.CrossRefPubMedGoogle Scholar
  3. 3.
    Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma—an attempt at a histo-clinical classification. Acta pathologica et microbiologica Scandinavica. 1965;64:31–49.PubMedGoogle Scholar
  4. 4.
    Stemmermann GN, Brown C. A survival study of intestinal and diffuse types of gastric carcinoma. Cancer. 1974;33(4):1190–5.CrossRefPubMedGoogle Scholar
  5. 5.
    Noda S, Soejima K, Inokuchi K. Clinicopathological analysis of the intestinal type and diffuse type of gastric carcinoma. The Japanese journal of surgery. 1980;10(4):277–83.CrossRefPubMedGoogle Scholar
  6. 6.
    Davessar K, Pezzullo JC, Kessimian N, Hale JH, Jauregui HO. Gastric adenocarcinoma: prognostic significance of several pathologic parameters and histologic classifications. Hum Pathol. 1990;21(3):325–32.CrossRefPubMedGoogle Scholar
  7. 7.
    Hasegawa S, Furukawa Y, Li M, Satoh S, Kato T, Watanabe T, Katagiri T, Tsunoda T, Yamaoka Y, Nakamura Y. Genome-wide analysis of gene expression in intestinal-type gastric cancers using a complementary DNA microarray representing 23,040 genes. Cancer Res. 2002;62(23):7012–7.PubMedGoogle Scholar
  8. 8.
    Jinawath N, Furukawa Y, Hasegawa S, Li M, Tsunoda T, Satoh S, Yamaguchi T, Imamura H, Inoue M, Shiozaki H, Nakamura Y. Comparison of gene-expression profiles between diffuse- and intestinal-type gastric cancers using a genome-wide cDNA microarray. Oncogene. 2004;23(40):6830–44. doi: 10.1038/sj.onc.1207886.CrossRefPubMedGoogle Scholar
  9. 9.
    Boussioutas A, Li H, Liu J, Waring P, Lade S, Holloway AJ, Taupin D, Gorringe K, Haviv I, Desmond PV, Bowtell DD. Distinctive patterns of gene expression in premalignant gastric mucosa and gastric cancer. Cancer Res. 2003;63(10):2569–77.PubMedGoogle Scholar
  10. 10.
    Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, Liu J, Yue YG. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med. 2015;21(5):449–56. doi: 10.1038/nm.3850.CrossRefPubMedGoogle Scholar
  11. 11.
    Hippo Y, Taniguchi H, Tsutsumi S, Machida N, Chong JM, Fukayama M, Kodama T, Aburatani H. Global gene expression analysis of gastric cancer by oligonucleotide microarrays. Cancer Res. 2002;62(1):233–40.PubMedGoogle Scholar
  12. 12.
    Lee S, Baek M, Yang H, Bang YJ, Kim WH, Ha JH, Kim DK, Jeoung DI. Identification of genes differentially expressed between gastric cancers and normal gastric mucosa with cDNA microarrays. Cancer Lett. 2002;184(2):197–206.CrossRefPubMedGoogle Scholar
  13. 13.
    Ooi CH, Ivanova T, Wu J, Lee M, Tan IB, Tao J, Ward L, Koo JH, Gopalakrishnan V, Zhu Y, Cheng LL, Lee J, Rha SY, Chung HC, Ganesan K, So J, Soo KC, Lim D, Chan WH, Wong WK, Bowtell D, Yeoh KG, Grabsch H, Boussioutas A, Tan P. Oncogenic pathway combinations predict clinical prognosis in gastric cancer. PLoS Genet. 2009;5(10):e1000676. doi: 10.1371/journal.pgen.1000676.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Muratani M, Deng N, Ooi WF, Lin SJ, Xing M, Xu C, Qamra A, Tay ST, Malik S, Wu J, Lee MH, Zhang S, Tan LL, Chua H, Wong WK, Ong HS, Ooi LL, Chow PK, Chan WH, Soo KC, Goh LK, Rozen S, Teh BT, Yu Q, Ng HH, Tan P. Nanoscale chromatin profiling of gastric adenocarcinoma reveals cancer-associated cryptic promoters and somatically acquired regulatory elements. Nat Commun. 2014;5:4361. doi: 10.1038/ncomms5361.CrossRefPubMedGoogle Scholar
  15. 15.
    Marisa L, de Reynies A, Duval A, Selves J, Gaub MP, Vescovo L, Etienne-Grimaldi MC, Schiappa R, Guenot D, Ayadi M, Kirzin S, Chazal M, Flejou JF, Benchimol D, Berger A, Lagarde A, Pencreach E, Piard F, Elias D, Parc Y, Olschwang S, Milano G, Laurent-Puig P, Boige V. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013;10(5):e1001453. doi: 10.1371/journal.pmed.1001453.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Thomas RM, Sobin LH. Gastrointestinal cancer. Cancer. 1995;75(1 Suppl):154–70.CrossRefPubMedGoogle Scholar
  17. 17.
    Adachi Y, Yasuda K, Inomata M, Sato K, Shiraishi N, Kitano S. Pathology and prognosis of gastric carcinoma: well versus poorly differentiated type. Cancer. 2000;89(7):1418–24.CrossRefPubMedGoogle Scholar
  18. 18.
    Kameda C, Nakamura M, Tanaka H, Yamasaki A, Kubo M, Tanaka M, Onishi H, Katano M. Oestrogen receptor-alpha contributes to the regulation of the hedgehog signalling pathway in ERalpha-positive gastric cancer. Br J Cancer. 2010;102(4):738–47. doi: 10.1038/sj.bjc.6605517.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sitarz R, Leguit RJ, de Leng WW, Morsink FH, Polkowski WP, Maciejewski R, Offerhaus GJ, Milne AN. Cyclooxygenase-2 mediated regulation of E-cadherin occurs in conventional but not early-onset gastric cancer cell lines. Cellular oncology: the official journal of the International Society for Cellular Oncology. 2009;31(6):475–85. doi: 10.3233/clo-2009-0496.Google Scholar
  20. 20.
    Saukkonen K, Nieminen O, van Rees B, Vilkki S, Harkonen M, Juhola M, Mecklin JP, Sipponen P, Ristimaki A. Expression of cyclooxygenase-2 in dysplasia of the stomach and in intestinal-type gastric adenocarcinoma. Clinical cancer research: an official journal of the American Association for Cancer Research. 2001;7(7):1923–31.Google Scholar
  21. 21.
    Okugawa Y, Tanaka K, Inoue Y, Kawamura M, Kawamoto A, Hiro J, Saigusa S, Toiyama Y, Ohi M, Uchida K, Mohri Y, Kusunoki M. Brain-derived neurotrophic factor/tropomyosin-related kinase B pathway in gastric cancer. Br J Cancer. 2013;108(1):121–30. doi: 10.1038/bjc.2012.499.CrossRefPubMedGoogle Scholar
  22. 22.
    Barber M, Murrell A, Ito Y, Maia AT, Hyland S, Oliveira C, Save V, Carneiro F, Paterson AL, Grehan N, Dwerryhouse S, Lao-Sirieix P, Caldas C, Fitzgerald RC. Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. J Pathol. 2008;216(3):295–306. doi: 10.1002/path.2426.CrossRefPubMedGoogle Scholar
  23. 23.
    La Vecchia C, Negri E, Franceschi S, Gentile A. Family history and the risk of stomach and colorectal cancer. Cancer. 1992;70(1):50–5.CrossRefPubMedGoogle Scholar
  24. 24.
    Vauhkonen M, Vauhkonen H, Sipponen P. Pathology and molecular biology of gastric cancer. Best Pract Res Clin Gastroenterol. 2006;20(4):651–74. doi: 10.1016/j.bpg.2006.03.016.CrossRefPubMedGoogle Scholar
  25. 25.
    Yasui W, Sentani K, Motoshita J, Nakayama H. Molecular pathobiology of gastric cancer. Scandinavian journal of surgery: SJS: official organ for the Finnish Surgical Society and the Scandinavian Surgical Society. 2006;95(4):225–31.Google Scholar
  26. 26.
    Campanella M, Casswell E, Chong S, Farah Z, Wieckowski MR, Abramov AY, Tinker A, Duchen MR. Regulation of mitochondrial structure and function by the F1Fo-ATPase inhibitor protein, IF1. Cell Metab. 2008;8(1):13–25. doi: 10.1016/j.cmet.2008.06.001.CrossRefPubMedGoogle Scholar
  27. 27.
    Shah DI, Takahashi-Makise N, Cooney JD, Li L, Schultz IJ, Pierce EL, Narla A, Seguin A, Hattangadi SM, Medlock AE, Langer NB, Dailey TA, Hurst SN, Faccenda D, Wiwczar JM, Heggers SK, Vogin G, Chen W, Chen C, Campagna DR, Brugnara C, Zhou Y, Ebert BL, Danial NN, Fleming MD, Ward DM, Campanella M, Dailey HA, Kaplan J, Paw BH. Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts. Nature. 2012;491(7425):608–12. doi: 10.1038/nature11536.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Formentini L, Sanchez-Arago M, Sanchez-Cenizo L, Cuezva JM. The mitochondrial ATPase inhibitory factor 1 triggers a ROS-mediated retrograde prosurvival and proliferative response. Mol Cell. 2012;45(6):731–42. doi: 10.1016/j.molcel.2012.01.008.CrossRefPubMedGoogle Scholar
  29. 29.
    Sanchez-Cenizo L, Formentini L, Aldea M, Ortega AD, Garcia-Huerta P, Sanchez-Arago M, Cuezva JM. Up-regulation of the ATPase inhibitory factor 1 (IF1) of the mitochondrial H+-ATP synthase in human tumors mediates the metabolic shift of cancer cells to a Warburg phenotype. J Biol Chem. 2010;285(33):25308–13. doi: 10.1074/jbc.M110.146480.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sanchez-Arago M, Formentini L, Martinez-Reyes I, Garcia-Bermudez J, Santacatterina F, Sanchez-Cenizo L, Willers IM, Aldea M, Najera L, Juarranz A, Lopez EC, Clofent J, Navarro C, Espinosa E, Cuezva JM. Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers. Oncogenesis. 2013;2:e46. doi: 10.1038/oncsis.2013.9.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Lim YS, Cha MK, Kim HK, Uhm TB, Park JW, Kim K, Kim IH. Removals of hydrogen peroxide and hydroxyl radical by thiol-specific antioxidant protein as a possible role in vivo. Biochem Biophys Res Commun. 1993;192(1):273–80. doi: 10.1006/bbrc.1993.1410.CrossRefPubMedGoogle Scholar
  32. 32.
    Besgen P, Trommler P, Vollmer S, Prinz JC. Ezrin, maspin, peroxiredoxin 2, and heat shock protein 27: potential targets of a streptococcal-induced autoimmune response in psoriasis. Journal of immunology (Baltimore, Md: 1950). 2010;184(9):5392–402. doi: 10.4049/jimmunol.0903520.CrossRefGoogle Scholar
  33. 33.
    Lomnytska MI, Becker S, Bodin I, Olsson A, Hellman K, Hellstrom AC, Mints M, Hellman U, Auer G, Andersson S. Differential expression of ANXA6, HSP27, PRDX2, NCF2, and TPM4 during uterine cervix carcinogenesis: diagnostic and prognostic value. Br J Cancer. 2011;104(1):110–9. doi: 10.1038/sj.bjc.6605992.CrossRefPubMedGoogle Scholar
  34. 34.
    Ji D, Li M, Zhan T, Yao Y, Shen J, Tian H, Zhang Z, Gu J. Prognostic role of serum AZGP1, PEDF and PRDX2 in colorectal cancer patients. Carcinogenesis. 2013;34(6):1265–72. doi: 10.1093/carcin/bgt056.CrossRefPubMedGoogle Scholar
  35. 35.
    Soini Y, Kallio JP, Hirvikoski P, Helin H, Kellokumpu-Lehtinen P, Kang SW, Tammela TL, Peltoniemi M, Martikainen PM, Kinnula VL. Oxidative/nitrosative stress and peroxiredoxin 2 are associated with grade and prognosis of human renal carcinoma. APMIS. 2006;114(5):329–37. doi: 10.1111/j.1600-0463.2006.apm_315.x.CrossRefPubMedGoogle Scholar
  36. 36.
    Hirahashi M, Koga Y, Kumagai R, Aishima S, Taguchi K, Oda Y. Induced nitric oxide synthetase and peroxiredoxin expression in intramucosal poorly differentiated gastric cancer of young patients. Pathol Int. 2014;64(4):155–63. doi: 10.1111/pin.12152.CrossRefPubMedGoogle Scholar
  37. 37.
    Weber IT, Steitz TA, Bubis J, Taylor SS. Predicted structures of cAMP binding domains of type I and II regulatory subunits of cAMP-dependent protein kinase. Biochemistry. 1987;26(2):343–51.CrossRefPubMedGoogle Scholar
  38. 38.
    Scott JD, Stofko RE, McDonald JR, Comer JD, Vitalis EA, Mangili JA. Type II regulatory subunit dimerization determines the subcellular localization of the cAMP-dependent protein kinase. J Biol Chem. 1990;265(35):21561–6.PubMedGoogle Scholar
  39. 39.
    Vincent-Dejean C, Cazabat L, Groussin L, Perlemoine K, Fumey G, Tissier F, Bertagna X, Bertherat J. Identification of a clinically homogenous subgroup of benign cortisol-secreting adrenocortical tumors characterized by alterations of the protein kinase A (PKA) subunits and high PKA activity. European journal of endocrinology/European Federation of Endocrine Societies. 2008;158(6):829–39. doi: 10.1530/EJE-07-0819.CrossRefGoogle Scholar
  40. 40.
    Kim SH, Ho JN, Jin H, Lee SC, Lee SE, Hong SK, Lee JW, Lee ES, Byun SS. Upregulated expression of BCL2, MCM7, and CCNE1 indicate cisplatin-resistance in the set of two human bladder cancer cell lines: T24 cisplatin sensitive and T24R2 cisplatin resistant bladder cancer cell lines. Investigative and clinical urology. 2016;57(1):63–72. doi: 10.4111/icu.2016.57.1.63.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kovo M, Kandli-Cohen M, Ben-Haim M, Galiani D, Carr DW, Dekel N. An active protein kinase A (PKA) is involved in meiotic arrest of rat growing oocytes. Reproduction (Cambridge, England). 2006;132(1):33–43. doi: 10.1530/rep.1.00824.CrossRefGoogle Scholar
  42. 42.
    Fax P, Carlson CR, Collas P, Tasken K, Esche H, Brockmann D. Binding of PKA-RIIalpha to the Adenovirus E1A12S oncoprotein correlates with its nuclear translocation and an increase in PKA-dependent promoter activity. Virology. 2001;285(1):30–41. doi: 10.1006/viro.2001.0926.CrossRefPubMedGoogle Scholar
  43. 43.
    Zynda ER, Matveev V, Makhanov M, Chenchik A, Kandel ES. Protein kinase A type II-alpha regulatory subunit regulates the response of prostate cancer cells to taxane treatment. Cell Cycle. 2014;13(20):3292–301. doi: 10.4161/15384101.2014.949501.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Mullenders J, Aranda-Orgilles B, Lhoumaud P, Keller M, Pae J, Wang K, Kayembe C, Rocha PP, Raviram R, Gong Y, Premsrirut PK, Tsirigos A, Bonneau R, Skok JA, Cimmino L, Hoehn D, Aifantis I. Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms. J Exp Med. 2015;212(11):1833–50. doi: 10.1084/jem.20151323.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Deardorff MA, Kaur M, Yaeger D, Rampuria A, Korolev S, Pie J, Gil-Rodriguez C, Arnedo M, Loeys B, Kline AD, Wilson M, Lillquist K, Siu V, Ramos FJ, Musio A, Jackson LS, Dorsett D, Krantz ID. Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet. 2007;80(3):485–94. doi: 10.1086/511888.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Mannini L, Liu J, Krantz ID, Musio A. Spectrum and consequences of SMC1A mutations: the unexpected involvement of a core component of cohesin in human disease. Hum Mutat. 2010;31(1):5–10. doi: 10.1002/humu.21129.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Barber TD, McManus K, Yuen KW, Reis M, Parmigiani G, Shen D, Barrett I, Nouhi Y, Spencer F, Markowitz S, Velculescu VE, Kinzler KW, Vogelstein B, Lengauer C, Hieter P. Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers. Proc Natl Acad Sci U S A. 2008;105(9):3443–8. doi: 10.1073/pnas.0712384105.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Cucco F, Servadio A, Gatti V, Bianchi P, Mannini L, Prodosmo A, De Vitis E, Basso G, Friuli A, Laghi L, Soddu S, Fontanini G, Musio A. Mutant cohesin drives chromosomal instability in early colorectal adenomas. Hum Mol Genet. 2014;23(25):6773–8. doi: 10.1093/hmg/ddu394.CrossRefPubMedGoogle Scholar
  49. 49.
    Thol F, Bollin R, Gehlhaar M, Walter C, Dugas M, Suchanek KJ, Kirchner A, Huang L, Chaturvedi A, Wichmann M, Wiehlmann L, Shahswar R, Damm F, Gohring G, Schlegelberger B, Schlenk R, Dohner K, Dohner H, Krauter J, Ganser A, Heuser M. Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications. Blood. 2014;123(6):914–20. doi: 10.1182/blood-2013-07-518746.CrossRefPubMedGoogle Scholar
  50. 50.
    Homme C, Krug U, Tidow N, Schulte B, Kuhler G, Serve H, Burger H, Berdel WE, Dugas M, Heinecke A, Buchner T, Koschmieder S, Muller-Tidow C. Low SMC1A protein expression predicts poor survival in acute myeloid leukemia. Oncol Rep. 2010;24(1):47–56.PubMedGoogle Scholar
  51. 51.
    Bragg AD, Das SS, Froehner SC. Dystrophin-associated protein scaffolding in brain requires alpha-dystrobrevin. Neuroreport. 2010;21(10):695–9. doi: 10.1097/WNR.0b013e32833b0a3b.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Jin H, Tan S, Hermanowski J, Bohm S, Pacheco S, McCauley JM, Greener MJ, Hinits Y, Hughes SM, Sharpe PT, Roberts RG. The dystrotelin, dystrophin and dystrobrevin superfamily: new paralogues and old isoforms. BMC Genomics. 2007;8:19. doi: 10.1186/1471-2164-8-19.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Hoshino S, Ohkoshi N, Ishii A, Shoji S. The expression of alpha-dystrobrevin and dystrophin during skeletal muscle regeneration. J Muscle Res Cell Motil. 2002;23(2):131–8.CrossRefPubMedGoogle Scholar
  54. 54.
    Albrecht DE, Froehner SC. Syntrophins and dystrobrevins: defining the dystrophin scaffold at synapses. Neurosignals. 2002;11(3):123–9.CrossRefPubMedGoogle Scholar
  55. 55.
    Compton AG, Cooper ST, Hill PM, Yang N, Froehner SC, North KN. The syntrophin-dystrobrevin subcomplex in human neuromuscular disorders. J Neuropathol Exp Neurol. 2005;64(4):350–61.CrossRefPubMedGoogle Scholar
  56. 56.
    Requena T, Cabrera S, Martin-Sierra C, Price SD, Lysakowski A, Lopez-Escamez JA. Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere’s disease. Hum Mol Genet. 2015;24(4):1119–26. doi: 10.1093/hmg/ddu524.CrossRefPubMedGoogle Scholar
  57. 57.
    de Toledo M, Senic-Matuglia F, Salamero J, Uze G, Comunale F, Fort P, Blangy A. The GTP/GDP cycling of rho GTPase TCL is an essential regulator of the early endocytic pathway. Mol Biol Cell. 2003;14(12):4846–56. doi: 10.1091/mbc.E03-04-0254.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Kawase K, Nakamura T, Takaya A, Aoki K, Namikawa K, Kiyama H, Inagaki S, Takemoto H, Saltiel AR, Matsuda M. GTP hydrolysis by the Rho family GTPase TC10 promotes exocytic vesicle fusion. Dev Cell. 2006;11(3):411–21. doi: 10.1016/j.devcel.2006.07.008.CrossRefPubMedGoogle Scholar
  59. 59.
    Han SW, Kim HP, Shin JY, Jeong EG, Lee WC, Kim KY, Park SY, Lee DW, Won JK, Jeong SY, Park KJ, Park JG, Kang GH, Seo JS, Kim JI, Kim TY. RNA editing in RHOQ promotes invasion potential in colorectal cancer. J Exp Med. 2014;211(4):613–21. doi: 10.1084/jem.20132209.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Ben Simon-Schiff E, Bach G, Zlotogora J, Abeliovich D. Combined enzymatic and linkage analysis for heterozygote detection in Hunter syndrome: identification of an apparent case of germinal mosaicism. Am J Med Genet. 1993;47(6):837–42. doi: 10.1002/ajmg.1320470608.CrossRefPubMedGoogle Scholar
  61. 61.
    Lualdi S, Tappino B, Di Duca M, Dardis A, Anderson CJ, Biassoni R, Thompson PW, Corsolini F, Di Rocco M, Bembi B, Regis S, Cooper DN, Filocamo M. Enigmatic in vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome. Hum Mutat. 2010;31(4):E1261–85. doi: 10.1002/humu.21208.CrossRefPubMedGoogle Scholar
  62. 62.
    Fasano L, Roder L, Core N, Alexandre E, Vola C, Jacq B, Kerridge S. The gene teashirt is required for the development of Drosophila embryonic trunk segments and encodes a protein with widely spaced zinc finger motifs. Cell. 1991;64(1):63–79.CrossRefPubMedGoogle Scholar
  63. 63.
    Manfroid I, Caubit X, Kerridge S, Fasano L. Three putative murine Teashirt orthologues specify trunk structures in Drosophila in the same way as the Drosophila teashirt gene. Development (Cambridge, England). 2004;131(5):1065–73. doi: 10.1242/dev.00977.CrossRefGoogle Scholar
  64. 64.
    Caubit X, Tiveron MC, Cremer H, Fasano L. Expression patterns of the three Teashirt-related genes define specific boundaries in the developing and postnatal mouse forebrain. J Comp Neurol. 2005;486(1):76–88. doi: 10.1002/cne.20500.CrossRefPubMedGoogle Scholar
  65. 65.
    Yamamoto M, Cid E, Bru S, Yamamoto F. Rare and frequent promoter methylation, respectively, of TSHZ2 and 3 genes that are both downregulated in expression in breast and prostate cancers. PLoS One. 2011;6(3):e17149. doi: 10.1371/journal.pone.0017149.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Karaca E, Buyukkaya R, Pehlivan D, Charng WL, Yaykasli KO, Bayram Y, Gambin T, Withers M, Atik MM, Arslanoglu I, Bolu S, Erdin S, Buyukkaya A, Yaykasli E, Jhangiani SN, Muzny DM, Gibbs RA, Lupski JR. Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome. J Clin Endocrinol Metab. 2015;100(1):E140–7. doi: 10.1210/jc.2014-1984.CrossRefPubMedGoogle Scholar
  67. 67.
    Mukhopadhyay S, Wen X, Ratti N, Loktev A, Rangell L, Scales SJ, Jackson PK. The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell. 2013;152(1–2):210–23. doi: 10.1016/j.cell.2012.12.026.CrossRefPubMedGoogle Scholar
  68. 68.
    Li BI, Matteson PG, Ababon MF, Nato Jr AQ, Lin Y, Nanda V, Matise TC, Millonig JH. The orphan GPCR, Gpr161, regulates the retinoic acid and canonical Wnt pathways during neurulation. Dev Biol. 2015;402(1):17–31. doi: 10.1016/j.ydbio.2015.02.007.CrossRefPubMedGoogle Scholar
  69. 69.
    Matteson PG, Desai J, Korstanje R, Lazar G, Borsuk TE, Rollins J, Kadambi S, Joseph J, Rahman T, Wink J, Benayed R, Paigen B, Millonig JH. The orphan G protein-coupled receptor, Gpr161, encodes the vacuolated lens locus and controls neurulation and lens development. Proc Natl Acad Sci U S A. 2008;105(6):2088–93. doi: 10.1073/pnas.0705657105.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Feigin ME, Xue B, Hammell MC, Muthuswamy SK. G-protein-coupled receptor GPR161 is overexpressed in breast cancer and is a promoter of cell proliferation and invasion. Proc Natl Acad Sci U S A. 2014;111(11):4191–6. doi: 10.1073/pnas.1320239111.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Cheng Zhang
    • 1
  • Li Min
    • 1
  • Jiafei Liu
    • 1
  • Wei Tian
    • 2
  • Yong Han
    • 3
  • Like Qu
    • 1
  • Chengchao Shou
    • 1
  1. 1.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular BiologyPeking University Cancer Hospital and InstituteBeijingChina
  2. 2.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Division of Cancer EtiologyPeking University Cancer Hospital & InstituteBeijingChina
  3. 3.Department of PathologyZhejiang Provincial People’s HospitalZhejiangChina

Personalised recommendations