Advertisement

Cellular and Molecular Life Sciences

, Volume 71, Issue 11, pp 2179–2192 | Cite as

Epigenetic identification of receptor tyrosine kinase-like orphan receptor 2 as a functional tumor suppressor inhibiting β-catenin and AKT signaling but frequently methylated in common carcinomas

  • Lili Li
  • Jianming Ying
  • Xin Tong
  • Lan Zhong
  • Xianwei Su
  • Tingxiu Xiang
  • Xingsheng Shu
  • Rong Rong
  • Lei Xiong
  • Hongyu Li
  • Anthony T. C. Chan
  • Richard F. Ambinder
  • Yajun GuoEmail author
  • Qian TaoEmail author
Research Article

Abstract

Through subtraction of tumor-specific CpG methylation, we identified receptor tyrosine kinase-like orphan receptor 2 (ROR2) as a candidate tumor suppressor gene (TSG). ROR2 is a specific receptor or co-receptor for WNT5A, involved in canonical and non-canonical WNT signaling, with its role in tumorigenesis controversial. We characterized its functions and related cell signaling in common carcinomas. ROR2 was frequently silenced by promoter CpG methylation in multiple carcinomas including nasopharyngeal, esophageal, gastric, colorectal, hepatocellular, lung, and breast cancers, while no direct correlation of ROR2 and WNT5A expression was observed. Ectopic expression of ROR2 resulted in tumor suppression independent of WNT5A status, through inhibiting tumor cell growth and inducing cell cycle arrest and apoptosis. ROR2 further suppressed epithelial-mesenchymal transition and tumor cell stemness through repressing β-catenin and AKT signaling, leading to further inhibition of tumor cell migration/invasion and increased chemo-sensitivity. Thus ROR2, as an epigenetically inactivated TSG, antagonizes both β-catenin and AKT signaling in multiple tumorigenesis. Its epigenetic silencing could be a potential tumor biomarker and therapeutic target for carcinomas.

Keywords

Epigenetic Tumor suppressor ROR2 Methylation Carcinoma 

Notes

Acknowledgments

We thank Drs. George Tsao, Sun Young Rha, Bert Vogelstein, and Michael Obster for some cell lines, DSMZ (German Collection of Microorganisms and Cell Cultures) for the KYSE cell lines (Shimada et al., Cancer 69: 277-284, 1992). This study was supported by grants from National Natural Science Foundation (No. 81372898 and 81172582), Hong Kong RGC (GRF # 474710), and Group Research Schemes of The Chinese University of Hong Kong.

Conflict of interest

The authors declare no conflicts of interest.

Supplementary material

18_2013_1485_MOESM1_ESM.pdf (9.7 mb)
Supplementary material 1 (PDF 9909 kb)
18_2013_1485_MOESM2_ESM.doc (88 kb)
Supplementary material 2 (DOC 88 kb)
18_2013_1485_MOESM3_ESM.doc (52 kb)
Supplementary material 3 (DOC 51 kb)

References

  1. 1.
    Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411(6835):355–365. doi: 10.1038/35077225 PubMedCrossRefGoogle Scholar
  2. 2.
    Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298(5600):1912–1934. doi: 10.1126/science.1075762 PubMedCrossRefGoogle Scholar
  3. 3.
    Gao B, Song H, Bishop K, Elliot G, Garrett L, English MA, Andre P, Robinson J, Sood R, Minami Y, Economides AN, Yang Y (2011) Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2. Dev Cell 20(2):163–176. doi: 10.1016/j.devcel.2011.01.001 PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Oldridge M, Fortuna AM, Maringa M, Propping P, Mansour S, Pollitt C, DeChiara TM, Kimble RB, Valenzuela DM, Yancopoulos GD, Wilkie AO (2000) Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B. Nat Genet 24(3):275–278. doi: 10.1038/73495 PubMedCrossRefGoogle Scholar
  5. 5.
    DeChiara TM, Kimble RB, Poueymirou WT, Rojas J, Masiakowski P, Valenzuela DM, Yancopoulos GD (2000) Ror2, encoding a receptor-like tyrosine kinase, is required for cartilage and growth plate development. Nat Genet 24(3):271–274. doi: 10.1038/73488 PubMedCrossRefGoogle Scholar
  6. 6.
    Maeda K, Kobayashi Y, Udagawa N, Uehara S, Ishihara A, Mizoguchi T, Kikuchi Y, Takada I, Kato S, Kani S, Nishita M, Marumo K, Martin TJ, Minami Y, Takahashi N (2012) Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med 18(3):405–412. doi: 10.1038/nm.2653 PubMedCrossRefGoogle Scholar
  7. 7.
    Takai A, Inomata H, Arakawa A, Yakura R, Matsuo-Takasaki M, Sasai Y (2010) Anterior neural development requires Del1, a matrix-associated protein that attenuates canonical Wnt signaling via the Ror2 pathway. Development 137(19):3293–3302. doi: 10.1242/dev.051136 PubMedCrossRefGoogle Scholar
  8. 8.
    Hikasa H, Shibata M, Hiratani I, Taira M (2002) The Xenopus receptor tyrosine kinase Xror2 modulates morphogenetic movements of the axial mesoderm and neuroectoderm via Wnt signaling. Development 129(22):5227–5239PubMedGoogle Scholar
  9. 9.
    Ford CE, Qian Ma SS, Quadir A, Ward RL (2012) The dual role of the novel Wnt receptor tyrosine kinase, ROR2, in human carcinogenesis. Int J Cancer. doi: 10.1002/ijc.27984 Google Scholar
  10. 10.
    Wright TM, Brannon AR, Gordan JD, Mikels AJ, Mitchell C, Chen S, Espinosa I, van de Rijn M, Pruthi R, Wallen E, Edwards L, Nusse R, Rathmell WK (2009) Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma. Oncogene 28(27):2513–2523. doi: 10.1038/onc.2009.116 PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Yamamoto H, Oue N, Sato A, Hasegawa Y, Matsubara A, Yasui W, Kikuchi A (2010) Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase. Oncogene 29(14):2036–2046. doi: 10.1038/onc.2009.496 PubMedCrossRefGoogle Scholar
  12. 12.
    O’Connell MP, Fiori JL, Xu M, Carter AD, Frank BP, Camilli TC, French AD, Dissanayake SK, Indig FE, Bernier M, Taub DD, Hewitt SM, Weeraratna AT (2009) The orphan tyrosine kinase receptor, ROR2, mediates Wnt5A signaling in metastatic melanoma. Oncogene 29(1):34–44. doi: 10.1038/onc.2009.305 PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Ren D, Minami Y, Nishita M (2011) Critical role of Wnt5a-Ror2 signaling in motility and invasiveness of carcinoma cells following Snail-mediated epithelial-mesenchymal transition. Genes Cells 16(3):304–315. doi: 10.1111/j.1365-2443.2011.01487.x PubMedCrossRefGoogle Scholar
  14. 14.
    Morioka K, Tanikawa C, Ochi K, Daigo Y, Katagiri T, Kawano H, Kawaguchi H, Myoui A, Yoshikawa H, Naka N, Araki N, Kudawara I, Ieguchi M, Nakamura K, Nakamura Y, Matsuda K (2009) Orphan receptor tyrosine kinase ROR2 as a potential therapeutic target for osteosarcoma. Cancer Sci 100(7):1227–1233. doi: 10.1111/j.1349-7006.2009.01165.x PubMedCrossRefGoogle Scholar
  15. 15.
    Edris B, Espinosa I, Muhlenberg T, Mikels A, Lee CH, Steigen SE, Zhu S, Montgomery KD, Lazar AJ, Lev D, Fletcher JA, Beck AH, West RB, Nusse R, van de Rijn M (2012) ROR2 is a novel prognostic biomarker and a potential therapeutic target in leiomyosarcoma and gastrointestinal stromal tumour. J Pathol. doi: 10.1002/path.3986 PubMedCentralPubMedGoogle Scholar
  16. 16.
    Lara E, Calvanese V, Huidobro C, Fernandez AF, Moncada-Pazos A, Obaya AJ, Aguilera O, Gonzalez-Sancho JM, Sanchez L, Astudillo A, Munoz A, Lopez-Otin C, Esteller M, Fraga MF (2010) Epigenetic repression of ROR2 has a Wnt-mediated, pro-tumourigenic role in colon cancer. Mol Cancer 9:170. doi: 10.1186/1476-4598-9-170 PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Geng M, Cao YC, Chen YJ, Jiang H, Bi LQ, Liu XH (2012) Loss of Wnt5a and Ror2 protein in hepatocellular carcinoma associated with poor prognosis. World J Gastroenterol 18(12):1328–1338. doi: 10.3748/wjg.v18.i12.1328 PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Grumolato L, Liu G, Mong P, Mudbhary R, Biswas R, Arroyave R, Vijayakumar S, Economides AN, Aaronson SA (2010) Canonical and noncanonical Wnts use a common mechanism to activate completely unrelated coreceptors. Genes Dev 24(22):2517–2530. doi: 10.1101/gad.1957710 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Mikels AJ, Nusse R (2006) Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context. PLoS Biol 4(4):e115. doi: 10.1371/journal.pbio.0040115 PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Mikels A, Minami Y, Nusse R (2009) Ror2 receptor requires tyrosine kinase activity to mediate Wnt5A signaling. J Biol Chem 284(44):30167–30176. doi: 10.1074/jbc.M109.041715 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Billiard J, Way DS, Seestaller-Wehr LM, Moran RA, Mangine A, Bodine PV (2005) The orphan receptor tyrosine kinase Ror2 modulates canonical Wnt signaling in osteoblastic cells. Mol Endocrinol 19(1):90–101. doi: 10.1210/me.2004-0153 PubMedCrossRefGoogle Scholar
  22. 22.
    Ho HY, Susman MW, Bikoff JB, Ryu YK, Jonas AM, Hu L, Kuruvilla R, Greenberg ME (2012) Wnt5a-Ror-dishevelled signaling constitutes a core developmental pathway that controls tissue morphogenesis. Proc Natl Acad Sci USA 109(11):4044–4051. doi: 10.1073/pnas.1200421109 PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Schambony A, Wedlich D (2007) Wnt-5A/Ror2 regulate expression of XPAPC through an alternative noncanonical signaling pathway. Dev Cell 12(5):779–792. doi: 10.1016/j.devcel.2007.02.016 PubMedCrossRefGoogle Scholar
  24. 24.
    Oishi I, Suzuki H, Onishi N, Takada R, Kani S, Ohkawara B, Koshida I, Suzuki K, Yamada G, Schwabe GC, Mundlos S, Shibuya H, Takada S, Minami Y (2003) The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway. Genes Cells 8(7):645–654 (pii 662)PubMedCrossRefGoogle Scholar
  25. 25.
    Takeuchi S, Takeda K, Oishi I, Nomi M, Ikeya M, Itoh K, Tamura S, Ueda T, Hatta T, Otani H, Terashima T, Takada S, Yamamura H, Akira S, Minami Y (2000) Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation. Genes Cells 5(1):71–78 (pii gtc300)PubMedCrossRefGoogle Scholar
  26. 26.
    Yamamoto S, Nishimura O, Misaki K, Nishita M, Minami Y, Yonemura S, Tarui H, Sasaki H (2008) Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex. Dev Cell 15(1):23–36. doi: 10.1016/j.devcel.2008.05.007 PubMedCrossRefGoogle Scholar
  27. 27.
    Ying J, Li H, Seng TJ, Langford C, Srivastava G, Tsao SW, Putti T, Murray P, Chan AT, Tao Q (2006) Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation. Oncogene 25(7):1070–1080. doi: 10.1038/sj.onc.1209154 PubMedCrossRefGoogle Scholar
  28. 28.
    Li L, Ying J, Li H, Zhang Y, Shu X, Fan Y, Tan J, Cao Y, Tsao SW, Srivastava G, Chan AT, Tao Q (2011) The human cadherin 11 is a pro-apoptotic tumor suppressor modulating cell stemness through Wnt/beta-catenin signaling and silenced in common carcinomas. Oncogene 31(34):3901–3912. doi: 10.1038/onc.2011.541 PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Seng TJ, Low JS, Li H, Cui Y, Goh HK, Wong ML, Srivastava G, Sidransky D, Califano J, Steenbergen RD, Rha SY, Tan J, Hsieh WS, Ambinder RF, Lin X, Chan AT, Tao Q (2007) The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation. Oncogene 26(6):934–944. doi: 10.1038/sj.onc.1209839 PubMedCrossRefGoogle Scholar
  30. 30.
    Tao Q, Huang H, Geiman TM, Lim CY, Fu L, Qiu GH, Robertson KD (2002) Defective de novo methylation of viral and cellular DNA sequences in ICF syndrome cells. Hum Mol Genet 11(18):2091–2102PubMedCrossRefGoogle Scholar
  31. 31.
    Tao Q, Swinnen LJ, Yang J, Srivastava G, Robertson KD, Ambinder RF (1999) Methylation status of the Epstein–Barr virus major latent promoter C in iatrogenic B cell lymphoproliferative disease. Application of PCR-based analysis. Am J Pathol 155(2):619–625. doi: 10.1016/S0002-9440(10)65157-7 PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Jin H, Wang X, Ying J, Wong AH, Cui Y, Srivastava G, Shen ZY, Li EM, Zhang Q, Jin J, Kupzig S, Chan AT, Cullen PJ, Tao Q (2007) Epigenetic silencing of a Ca(2+)-regulated Ras GTPase-activating protein RASAL defines a new mechanism of Ras activation in human cancers. Proc Natl Acad Sci USA 104(30):12353–12358. doi: 10.1073/pnas.0700153104 PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Ying J, Li H, Yu J, Ng KM, Poon FF, Wong SC, Chan AT, Sung JJ, Tao Q (2008) WNT5A exhibits tumor-suppressive activity through antagonizing the Wnt/beta-catenin signaling, and is frequently methylated in colorectal cancer. Clin Cancer Res 14(1):55–61. doi: 10.1158/1078-0432.CCR-07-1644 PubMedCrossRefGoogle Scholar
  34. 34.
    Hu XT, Zhang FB, Fan YC, Shu XS, Wong AH, Zhou W, Shi QL, Tang HM, Fu L, Guan XY, Rha SY, Tao Q, He C (2009) Phospholipase C delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer. Oncogene 28(26):2466–2475. doi: 10.1038/onc.2009.92 PubMedCrossRefGoogle Scholar
  35. 35.
    Wang Y, Li J, Cui Y, Li T, Ng KM, Geng H, Li H, Shu XS, Liu W, Luo B, Zhang Q, Mok TS, Zheng W, Qiu X, Srivastava G, Yu J, Sung JJ, Chan AT, Ma D, Tao Q, Han W (2009) CMTM3, located at the critical tumor suppressor locus 16q22.1, is silenced by CpG methylation in carcinomas and inhibits tumor cell growth through inducing apoptosis. Cancer Res 69(12):5194–5201. doi: 10.1158/0008-5472.CAN-08-3694 PubMedCrossRefGoogle Scholar
  36. 36.
    Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM (2004) ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6(1):1–6PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3(6):415–428. doi: 10.1038/nrg816nrg816 PubMedGoogle Scholar
  38. 38.
    Baylin SB, Ohm JE (2006) Epigenetic gene silencing in cancer—a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 6(2):107–116. doi: 10.1038/nrc1799 PubMedCrossRefGoogle Scholar
  39. 39.
    Ushijima T (2005) Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer 5(3):223–231. doi: 10.1038/nrc1571 PubMedCrossRefGoogle Scholar
  40. 40.
    Ying J, Srivastava G, Hsieh WS, Gao Z, Murray P, Liao SK, Ambinder R, Tao Q (2005) The stress-responsive gene GADD45G is a functional tumor suppressor, with its response to environmental stresses frequently disrupted epigenetically in multiple tumors. Clin Cancer Res 11(18):6442–6449. doi: 10.1158/1078-0432.CCR-05-0267 PubMedCrossRefGoogle Scholar
  41. 41.
    Qiu GH, Salto-Tellez M, Ross JA, Yeo W, Cui Y, Wheelhouse N, Chen GG, Harrison D, Lai P, Tao Q, Hooi SC (2008) The tumor suppressor gene DLEC1 is frequently silenced by DNA methylation in hepatocellular carcinoma and induces G1 arrest in cell cycle. J Hepatol 48(3):433–441. doi: 10.1016/j.jhep.2007.11.015 PubMedCrossRefGoogle Scholar
  42. 42.
    Li X, Cheung KF, Ma X, Tian L, Zhao J, Go MY, Shen B, Cheng AS, Ying J, Tao Q, Sung JJ, Kung HF, Yu J (2011) Epigenetic inactivation of paired box gene 5, a novel tumor suppressor gene, through direct upregulation of p53 is associated with prognosis in gastric cancer patients. Oncogene 31(29):3419–3430. doi: 10.1038/onc.2011.511 PubMedCrossRefGoogle Scholar
  43. 43.
    Yu J, Cheng YY, Tao Q, Cheung KF, Lam CN, Geng H, Tian LW, Wong YP, Tong JH, Ying JM, Jin H, To KF, Chan FK, Sung JJ (2009) Methylation of protocadherin 10, a novel tumor suppressor, is associated with poor prognosis in patients with gastric cancer. Gastroenterology 136(2):640 e641–651 e641. doi: 10.1053/j.gastro.2008.10.050 CrossRefGoogle Scholar
  44. 44.
    Green JL, Kuntz SG, Sternberg PW (2008) Ror receptor tyrosine kinases: orphans no more. Trends Cell Biol 18(11):536–544. doi: 10.1016/j.tcb.2008.08.006 PubMedCrossRefGoogle Scholar
  45. 45.
    Chen Y, Bellamy WP, Seabra MC, Field MC, Ali BR (2005) ER-associated protein degradation is a common mechanism underpinning numerous monogenic diseases including Robinow syndrome. Hum Mol Genet 14(17):2559–2569. doi: 10.1093/hmg/ddi259 PubMedCrossRefGoogle Scholar
  46. 46.
    Liu Y, Ross JF, Bodine PV, Billiard J (2007) Homodimerization of Ror2 tyrosine kinase receptor induces 14-3-3(beta) phosphorylation and promotes osteoblast differentiation and bone formation. Mol Endocrinol 21(12):3050–3061. doi: 10.1210/me.2007-0323 PubMedCrossRefGoogle Scholar
  47. 47.
    Kani S, Oishi I, Yamamoto H, Yoda A, Suzuki H, Nomachi A, Iozumi K, Nishita M, Kikuchi A, Takumi T, Minami Y (2004) The receptor tyrosine kinase Ror2 associates with and is activated by casein kinase iepsilon. J Biol Chem 279(48):50102–50109. doi: 10.1074/jbc.M409039200 PubMedCrossRefGoogle Scholar
  48. 48.
    Li J, Ying J, Fan Y, Wu L, Ying Y, Chan AT, Srivastava G, Tao Q (2010) WNT5A antagonizes WNT/beta-catenin signaling and is frequently silenced by promoter CpG methylation in esophageal squamous cell carcinoma. Cancer Biol Ther 10(6):617–624. doi:http://www.ncbi.nlm.nih.gov/pubmed/20603606 PubMedCrossRefGoogle Scholar
  49. 49.
    Lee JM, Dedhar S, Kalluri R, Thompson EW (2006) The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol 172(7):973–981. doi: 10.1083/jcb.200601018 PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Maugeri-Sacca M, Vigneri P, De Maria R (2011) Cancer stem cells and chemosensitivity. Clin Cancer Res 17(15):4942–4947. doi: 10.1158/1078-0432.CCR-10-2538 PubMedCrossRefGoogle Scholar
  51. 51.
    Yamaguchi T, Yanagisawa K, Sugiyama R, Hosono Y, Shimada Y, Arima C, Kato S, Tomida S, Suzuki M, Osada H, Takahashi T (2012) NKX2-1/TITF1/TTF-1-Induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. Cancer Cell 21(3):348–361. doi: 10.1016/j.ccr.2012.02.008 PubMedCrossRefGoogle Scholar
  52. 52.
    Zhang S, Chen L, Cui B, Chuang HY, Yu J, Wang-Rodriguez J, Tang L, Chen G, Basak GW, Kipps TJ (2012) ROR1 is expressed in human breast cancer and associated with enhanced tumor-cell growth. PLoS One 7(3):e31127. doi: 10.1371/journal.pone.0031127 PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Broome HE, Rassenti LZ, Wang HY, Meyer LM, Kipps TJ (2011) ROR1 is expressed on hematogones (non-neoplastic human B-lymphocyte precursors) and a minority of precursor-B acute lymphoblastic leukemia. Leuk Res 35(10):1390–1394. doi: 10.1016/j.leukres.2011.06.021 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  • Lili Li
    • 1
  • Jianming Ying
    • 1
  • Xin Tong
    • 2
    • 3
  • Lan Zhong
    • 1
  • Xianwei Su
    • 1
  • Tingxiu Xiang
    • 4
  • Xingsheng Shu
    • 1
  • Rong Rong
    • 1
  • Lei Xiong
    • 1
  • Hongyu Li
    • 1
  • Anthony T. C. Chan
    • 1
  • Richard F. Ambinder
    • 5
  • Yajun Guo
    • 2
    • 3
    Email author
  • Qian Tao
    • 1
    • 5
    Email author
  1. 1.Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health SciencesThe Chinese University of Hong Kong and CUHK Shenzhen Research InstituteShatinHong Kong
  2. 2.PLA General Hospital Cancer CenterBeijingChina
  3. 3.Cancer InstituteSecond Military Medical UniversityShanghaiChina
  4. 4.The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
  5. 5.Johns Hopkins Singapore and Sydney Kimmel Comprehensive Cancer CenterJohns Hopkins School of MedicineBaltimoreUSA

Personalised recommendations