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Metformin sensitizes endometrial cancer cells to chemotherapy through IDH1-induced Nrf2 expression via an epigenetic mechanism

Oncogenevolume 37pages56665681 (2018) | Download Citation

Abstract

Chemoresistance is the major obstacle to cure endometrial cancer, whereas metformin has demonstrated sensitization to chemotherapy in endometrial cancer. A novel finding states that isocitrate dehydrogenase 1 (IDH1) involves in cancer chemoresistance. Recent studies have revealed that epigenetic modifications facilitate chemoresistance. However, whether IDH1 play a role in metformin-induced endometrial cancer chemosensitivity through epigenetic modification is incompletely understood. Immunohistochemistry and Elisa assays were used to evaluate the expression pattern of IDH1 in endometrial tissue and serum, respectively. Western blot was performed to determine changes in expression of key molecules in the IDH1-ɑ-KG-TET1-Nrf2 signaling pathway after various treatments. Dot blot assays were used to assess global hydroxymethylation levels after metformin administration or plasmid transfection. Antioxidant response element (ARE) activity in the IDH1 promoter region was monitored by luciferase assay. Cancer cell sensitivity to chemotherapy was detected by SRB assay. We found that activation of the IDH1 signaling pathway in endometrial cancer tissue resulting from aberrant expression of IDH1 and its downstream mediators conferred chemoresistance. We found that this effect was abated by metformin treatment. Dot blot and HMeDIP assays revealed that metformin blocked IDH1-ɑ-KG-TET1-mediated enhancement of Nrf2 hydroxymethylation levels, eliminating chemoresistance. Moreover, we observed that chemoresistance was enhanced via a regulatory loop in which Nrf2 activated IDH1-ɑ-KG-TET1-Nrf2 signaling via binding to the ARE sites in the IDH1 promoter region. Our findings highlight a critical role of IDH1-ɑ-KG-TET1-Nrf2 signaling in chemoresistance and suggest that rational combination therapy with metformin and chemotherapeutics has the potential to suppress chemoresistance.

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References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.

  2. 2.

    Wei KR, C W, Zhang SW, Zheng RS, Wang YN, Liang ZH. Epidemiology of uterine corpus cancer in some cancer registering areas of China from 2003 to 2007. Chin J Obstet Gynecol. 2012;47:445–51.

  3. 3.

    Wei KR, C W, Zhang SW, Zheng RS, Liang ZH. An analysis of incidence and mortality of corpus uteri cancer in China, 2009. China Cancer. 2013;22:605–11.

  4. 4.

    Sorosky JI. Endometrial cancer. Obstet Gynecol. 2012;120:383–97.

  5. 5.

    Chaudhry P, Asselin E. Resistance to chemotherapy and hormone therapy in endometrial cancer. Endocr Relat Cancer. 2009;16:363–80.

  6. 6.

    J T, Chen N, Zhao F, W XJ, Kong B, Z W, et al. High levels of Nrf2 determine chemoresistance in type II endometrial cancer. Cancer Res. 2010;70:5486–96.

  7. 7.

    Saygin C, Wiechert A, Rao VS, Alluri R, Connor E, Thiagarajan PS, et al. CD55 regulates self-renewal and cisplatin resistance in endometrioid tumors. J Exp Med. 2017;214:2715–32.

  8. 8.

    Hernandez AV, Pasupuleti V, Benites-Zapata VA, Thota P, Deshpande A, Perez-Lopez FR. Insulin resistance and endometrial cancer risk: a systematic review and meta-analysis. Eur J Cancer. 2015;51:2747–58.

  9. 9.

    Goodwin PJ, Ligibel JA, Stambolic V. Metformin in breast cancer: time for action. J Clin Oncol. 2009;27:3271–3.

  10. 10.

    Wang LW, Li ZS, Zou DW, Jin ZD, Gao J, Xu GM. Metformin induces apoptosis of pancreatic cancer cells. World J Gastroenterol. 2008;14:7192–8.

  11. 11.

    Tan BK, Adya R, Chen J, Lehnert H, Sant Cassia LJ, Randeva HS. Metformin treatment exerts antiinvasive and antimetastatic effects in human endometrial carcinoma cells. J Clin Endocrinol Metab. 2011;96:808–16.

  12. 12.

    El-Ashmawy NE, Khedr NF, El-Bahrawy HA, Abo Mansour HE. Metformin augments doxorubicin cytotoxicity in mammary carcinoma through activation of adenosine monophosphate protein kinase pathway. Tumour Biol. 2017;39:1010428317692235.

  13. 13.

    Cuyas E, Martin-Castillo B, Bosch-Barrera J, Menendez JA. Metformin inhibits RANKL and sensitizes cancer stem cells to denosumab. Cell Cycle. 2017;16:1022–8.

  14. 14.

    Li B, Li X, Ni Z, Zhang Y, Zeng Y, Yan X, et al. Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells. Oncotarget. 2016;7:59458–70.

  15. 15.

    Matassa DS, Amoroso MR, Lu H, Avolio R, Arzeni D, Procaccini C, et al. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer. Cell Death Differ. 2016;23:1542–54.

  16. 16.

    Yu G, Fang W, Xia T, Chen Y, Gao Y, Jiao X, et al. Metformin potentiates rapamycin and cisplatin in gastric cancer in mice. Oncotarget. 2015;6:12748–62.

  17. 17.

    Hanna RK, Zhou C, Malloy KM, Sun L, Zhong Y, Gehrig PA, et al. Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. Gynecol Oncol. 2012;125:458–69.

  18. 18.

    Zhang Y, Guan M, Zheng Z, Zhang Q, Gao F, Xue Y. Effects of metformin on CD133+ colorectal cancer cells in diabetic patients. PLoS ONE. 2013;8:e81264.

  19. 19.

    Zhuo Z, Wang A, Yu H. Metformin targeting autophagy overcomes progesterone resistance in endometrial carcinoma. Arch Gynecol Obstet. 2016;294:1055–61.

  20. 20.

    Zarei M, Lal S, Parker SJ, Nevler A, Vaziri-Gohar A, Dukleska K, et al. Posttranscriptional upregulation of IDH1 by HuR establishes a powerful survival phenotype in pancreatic cancer cells. Cancer Res. 2017;77:4460–71.

  21. 21.

    Calvert AE, Chalastanis A, Wu Y, Hurley LA, Kouri FM, Bi Y, et al. Cancer-associated IDH1 promotes growth and resistance to targeted therapies in the absence of mutation. Cell Rep. 2017;19:1858–73.

  22. 22.

    Wang J-B, Dong D-F, Wang M-D, Gao K. IDH1 overexpression induced chemotherapy resistance and IDH1 mutation enhanced chemotherapy sensitivity in glioma cells in vitro and in vivo. Asian Pac J Cancer Prev. 2014;15:427–32.

  23. 23.

    Yang SH, Li S, Lu G, Xue H, Kim DH, Zhu JJ, et al. Metformin treatment reduces temozolomide resistance of glioblastoma cells. Oncotarget. 2016;7:78787–803.

  24. 24.

    Valtorta S, Dico AL, Raccagni I, Gaglio D, Belloli S, Politi LS, et al. Metformin and temozolomide, a synergic option to overcome resistance in glioblastoma multiforme models. Oncotarget. 2017;8:113090–104.

  25. 25.

    Ma QL, Wang JH, Wang YG, Hu C, Mu QT, Yu MX, et al. High IDH1 expression is associated with a poor prognosis in cytogenetically normal acute myeloid leukemia. Int J Cancer. 2015;137:1058–65.

  26. 26.

    Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009;324:930–5.

  27. 27.

    Kastl L, Brown I, Schofield AC. Altered DNA methylation is associated with docetaxel resistance in human breast cancer cells. Int J Oncol. 2010;36:1235–41.

  28. 28.

    Kwon OH, Park JL, Baek SJ, Noh SM, Song KS, Kim SY, et al. Aberrant upregulation of ASCL2 by promoter demethylation promotes the growth and resistance to 5-fluorouracil of gastric cancer cells. Cancer Sci. 2013;104:391–7.

  29. 29.

    Kang KA, Piao MJ, Kim KC, Kang HK, Chang WY, Park IC, et al. Epigenetic modification of Nrf2 in 5-fluorouracil-resistant colon cancer cells: involvement of TET-dependent DNA demethylation. Cell Death Dis. 2014;5:e1183.

  30. 30.

    Rushmore TH, Morton MR, Pickett CB. The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem. 1991;266:11632–9.

  31. 31.

    Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89–116.

  32. 32.

    Khor TO, Yu S, Kong AN. Dietary cancer chemopreventive agents - targeting inflammation and Nrf2 signaling pathway. Planta Med. 2008;74:1540–7.

  33. 33.

    Yates MS, Tauchi M, Katsuoka F, Flanders KC, Liby KT, Honda T, et al. Pharmacodynamic characterization of chemopreventive triterpenoids as exceptionally potent inducers of Nrf2-regulated genes. Mol Cancer Ther. 2007;6:154–62.

  34. 34.

    Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev. 2006;38:769–89.

  35. 35.

    MacLeod AK, McMahon M, Plummer SM, Higgins LG, Penning TM, Igarashi K, et al. Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds. Carcinogenesis. 2009;30:1571–80.

  36. 36.

    Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012;22:66–79.

  37. 37.

    Kim YR, Oh JE, Kim MS, Kang MR, Park SW, Han JY, et al. Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J Pathol. 2010;220:446–51.

  38. 38.

    Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, Hoque MO, et al. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006;3:e420.

  39. 39.

    Ohta T, Iijima K, Miyamoto M, Nakahara I, Tanaka H, Ohtsuji M, et al. Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res. 2008;68:1303–9.

  40. 40.

    Stacy DR, Ely K, Massion PP, Yarbrough WG, Hallahan DE, Sekhar KR, et al. Increased expression of nuclear factor E2 p45-related factor 2 (NRF2) in head and neck squamous cell carcinomas. Head Neck. 2006;28:813–8.

  41. 41.

    Zhang P, Singh A, Yegnasubramanian S, Esopi D, Kombairaju P, Bodas M, et al. Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Mol Cancer Ther. 2010;9:336–46.

  42. 42.

    Ikeda H, Nishi S, Sakai M. Transcription factor Nrf2/MafK regulates rat placental glutathione S-transferase gene during hepatocarcinogenesis. Biochem J. 2004;380:515–21.

  43. 43.

    Cho JM, Manandhar S, Lee HR, Park HM, Kwak MK. Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: implication to cancer cell resistance. Cancer Lett. 2008;260:96–108.

  44. 44.

    Shim GS, Manandhar S, Shin DH, Kim TH, Kwak MK. Acquisition of doxorubicin resistance in ovarian carcinoma cells accompanies activation of the NRF2 pathway. Free Radic Biol Med. 2009;47:1619–31.

  45. 45.

    Singh A, Boldin-Adamsky S, Thimmulappa RK, Rath SK, Ashush H, Coulter J, et al. RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy. Cancer Res. 2008;68:7975–84.

  46. 46.

    Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, et al. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis. 2008;29:1235–43.

  47. 47.

    Chen N, Yi X, Abushahin N, Pang S, Zhang D, Kong B, et al. Nrf2 expression in endometrial serous carcinomas and its precancers. Int J Clin Exp Pathol. 2010;4:85–96.

  48. 48.

    Chin RM, Fu X, Pai MY, Vergnes L, Hwang H, Deng G, et al. The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014;510:397–401.

  49. 49.

    Dong L, Zhou Q, Zhang Z, Zhu Y, Duan T, Feng Y. Metformin sensitizes endometrial cancer cells to chemotherapy by repressing glyoxalase I expression. J Obstet Gynaecol Res. 2012;38:1077–85.

  50. 50.

    Liu Y, He C, Huang X. Metformin partially reverses the carboplatin-resistance in NSCLC by inhibiting glucose metabolism. Oncotarget. 2017;8:75206–16.

  51. 51.

    Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60:1577–85.

  52. 52.

    SongTao Q, Lei Y, Si G, YanQing D, HuiXia H, XueLin Z, et al. IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma. Cancer Sci. 2012;103:269–73.

  53. 53.

    Houillier C, Wang X, Kaloshi G, Mokhtari K, Guillevin R, Laffaire J, et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology. 2010;75:1560–6.

  54. 54.

    Cairncross JG, Wang M, Jenkins RB, Shaw EG, Giannini C, Brachman DG, et al. Benefit from procarbazine, lomustine, and vincristine in oligodendroglial tumors is associated with mutation of IDH. J Clin Oncol. 2014;32:783–90.

  55. 55.

    Jia L, Liu Y, Yi X, Miron A, Crum CP, Kong B, et al. Endometrial glandular dysplasia with frequent p53 gene mutation: a genetic evidence supporting its precancer nature for endometrial serous carcinoma. Clin Cancer Res. 2008;14:2263–9.

  56. 56.

    Xiang L, Zheng W, Kong B. Detection of PAX8 and p53 is beneficial in recognizing metastatic carcinomas in pelvic washings, especially in cases with suspicious cytology. Gynecol Oncol. 2012;127:595–600.

  57. 57.

    Fadare O, Gwin K, Desouki MM, Crispens MA, Jones HW 3rd, Khabele D, et al. The clinicopathologic significance of p53 and BAF-250a (ARID1A) expression in clear cell carcinoma of the endometrium. Mod Pathol. 2013;26:1101–10.

  58. 58.

    Hu X, Yu AX, Qi BW, Fu T, Wu G, Zhou M, et al. The expression and significance of IDH1 and p53 in osteosarcoma. J Exp Clin Cancer Res. 2010;29:43.

  59. 59.

    Ogura R, Tsukamoto Y, Natsumeda M, Isogawa M, Aoki H, Kobayashi T, et al. Immunohistochemical profiles of IDH1, MGMT and P53: practical significance for prognostication of patients with diffuse gliomas. Neuropathol. 2015;35:324–35.

  60. 60.

    Montgomery RM, Queiroz Lde S, Rogerio F. EGFR, p53, IDH-1 and MDM2 immunohistochemical analysis in glioblastoma: therapeutic and prognostic correlation. Arq Neuropsiquiatr. 2015;73:561–8.

  61. 61.

    Sun N, Chen Z, Tan F, Zhang B, Yao R, Zhou C, et al. Isocitrate dehydrogenase 1 is a novel plasma biomarker for the diagnosis of non-small cell lung cancer. Clin Cancer Res. 2013;19:5136–45.

  62. 62.

    Molenaar RJ, Botman D, Smits MA, Hira VV, van Lith SA, Stap J, et al. Radioprotection of IDH1-mutated cancer cells by the IDH1-mutant inhibitor AGI-5198. Cancer Res. 2015;75:4790–802.

  63. 63.

    Lu Y, Kwintkiewicz J, Liu Y, Tech K, Frady LN, Su YT, et al. Chemosensitivity of IDH1-mutated gliomas due to an impairment in PARP1-mediated DNA repair. Cancer Res. 2017;77:1709–18.

  64. 64.

    Gasparre G, Kurelac I, Capristo M, Iommarini L, Ghelli A, Ceccarelli C, et al. A mutation threshold distinguishes the antitumorigenic effects of the mitochondrial gene MTND1, an oncojanus function. Cancer Res. 2011;71:6220–9.

  65. 65.

    Vatrinet R, Leone G, De Luise M, Girolimetti G, Vidone M, Gasparre G, et al. The alpha-ketoglutarate dehydrogenase complex in cancer metabolic plasticity. Cancer Metab. 2017;5:3.

  66. 66.

    Tanaka K, Sasayama T, Irino Y, Takata K, Nagashima H, Satoh N, et al. Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment. J Clin Invest. 2015;125:1591–602.

  67. 67.

    Bajpai R, Matulis SM, Wei C, Nooka AK, Von Hollen HE, Lonial S, et al. Targeting glutamine metabolism in multiple myeloma enhances BIM binding to BCL-2 eliciting synthetic lethality to venetoclax. Oncogene. 2016;35:3955–64.

  68. 68.

    Keenan MM, Liu B, Tang X, Wu J, Cyr D, Stevens RD, et al. ACLY and ACC1 regulate hypoxia-induced apoptosis by modulating ETV4 via alpha-ketoglutarate. PLoS Genet. 2015;11:e1005599.

  69. 69.

    Zhang Z, Dong L, Sui L, Yang Y, Liu X, Yu Y, et al. Metformin reverses progestin resistance in endometrial cancer cells by downregulating GloI expression. Int J Gynecol Cancer. 2011;21:213–21.

  70. 70.

    Feinberg AP, Koldobskiy MA, Gondor A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Genet. 2016;17:284–99.

  71. 71.

    Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19:17–30.

  72. 72.

    Xu T, Brandmaier S, Messias AC, Herder C, Draisma HH, Demirkan A, et al. Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. Diabetes Care. 2015;38:1858–67.

  73. 73.

    Antony S, Jiang G, Wu Y, Meitzler JL, Makhlouf HR, Haines DC, et al. NADPH oxidase 5 (NOX5)-induced reactive oxygen signaling modulates normoxic HIF-1alpha and p27(Kip1) expression in malignant melanoma and other human tumors. Mol Carcinog. 2017;56:2643–62.

  74. 74.

    Nanduri J, Vaddi DR, Khan SA, Wang N, Makarenko V, Semenza GL, et al. HIF-1alpha activation by intermittent hypoxia requires NADPH oxidase stimulation by xanthine oxidase. PLoS ONE. 2015;10:e0119762.

  75. 75.

    Chen HF, Wu KJ. Epigenetics, TET proteins, and hypoxia in epithelial-mesenchymal transition and tumorigenesis. Biomedicine. 2016;6:1.

  76. 76.

    Tsai YP, Chen HF, Chen SY, Cheng WC, Wang HW, Shen ZJ, et al. TET1 regulates hypoxia-induced epithelial-mesenchymal transition by acting as a co-activator. Genome Biol. 2014;15:513.

  77. 77.

    Wang Y, Wang Y, Zhang Z, Park JY, Guo D, Liao H, et al. Mechanism of progestin resistance in endometrial precancer/cancer through Nrf2-AKR1C1 pathway. Oncotarget. 2016;7:10363–72.

  78. 78.

    Do MT, Kim HG, Choi JH, Jeong HG. Metformin induces microRNA-34a to downregulate the Sirt1/Pgc-1alpha/Nrf2 pathway, leading to increased susceptibility of wild-type p53 cancer cells to oxidative stress and therapeutic agents. Free Radic Biol Med. 2014;74:21–34.

  79. 79.

    Zhang HH, Guo XL. Combinational strategies of metformin and chemotherapy in cancers. Cancer Chemother Pharmacol. 2016;78:13–26.

  80. 80.

    Meireles CG, Pereira SA, Valadares LP, Rego DF, Simeoni LA, Guerra ENS, et al. Effects of metformin on endometrial cancer: Systematic review and meta-analysis. Gynecol Oncol. 2017;147:167–80.

  81. 81.

    Zhang Z, Zhou D, Lai Y, Liu Y, Tao X, Wang Q, et al. Estrogen induces endometrial cancer cell proliferation and invasion by regulating the fat mass and obesity-associated gene via PI3K/AKT and MAPK signaling pathways. Cancer Lett. 2012;319:89–97.

  82. 82.

    Chen J, Bai M, Ning C, Xie B, Zhang J, Liao H, et al. Gankyrin facilitates follicle-stimulating hormone-driven ovarian cancer cell proliferation through the PI3K/AKT/HIF-1alpha/cyclin D1 pathway. Oncogene. 2016;35:2506–17.

  83. 83.

    Lv QY, Xie BY, Yang BY, Ning CC, Shan WW, Gu C, et al. Increased TET1 expression in inflammatory microenvironment of hyperinsulinemia enhances the response of endometrial cancer to estrogen by epigenetic modulation of GPER. J Cancer. 2017;8:894–902.

  84. 84.

    Ning C, Xie B, Zhang L, Li C, Shan W, Yang B, et al. Infiltrating macrophages induce ERalpha expression through an IL17A-mediated epigenetic mechanism to sensitize endometrial cancer cells to estrogen. Cancer Res. 2016;76:1354–66.

  85. 85.

    Tao X, Zhao N, Jin H, Zhang Z, Liu Y, Wu J, et al. FSH enhances the proliferation of ovarian cancer cells by activating transient receptor potential channel C3. Endocr Relat Cancer. 2013;20:415–29.

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Acknowledgements

We thank Prof. Zhao Shimin (Fudan University, Shanghai, China) for providing the plasmids pcDNA3.0-TET1-flag and pRSF-Duet1-IDH1. We also thank Prof. Shi Yujiang (Harvard University, Cambridge, MA) for providing pPB-TET1 plasmid. This work was supported by grants from the National Natural Science Foundation of China (grant numbers 81672562, 81370074), the Shanghai Municipal Public Health Bureau (grant number XYQ2013119) and the “Chenxing Project” from Shanghai Jiao Tong University to ZZ. The work was also partially supported by the Mark and Jane Gibson distinguished professorship endowment fund to WZ. We thank Dr. Yinhua Yu (The University of Texas, M.D. Anderson Cancer Center) for helpful discussions.

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  1. These authors contributed equally: Mingzhu Bai, Linlin Yang, Hong Liao.

Affiliations

  1. Reproductive Medicine Center, Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, 200080, China

    • Mingzhu Bai
    • , Linlin Yang
    • , Bingying Xie
    • , Youji Feng
    •  & Zhenbo Zhang
  2. Department of Obstetrics and Gynecology, Shanghai First People’s Hospital, Baoshan Branch, Shanghai, 201900, China

    • Linlin Yang
    • , Xiaoyan Liang
    • , Xiong Chen
    •  & Zhenbo Zhang
  3. Department of Cervical Diseases, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040, China

    • Hong Liao
  4. Department of Pathology, Huashan Hospital of Fudan University, Shanghai, 200040, China

    • Ji Xiong
  5. Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China

    • Xiang Tao
  6. Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, 200011, China

    • Yali Cheng
    •  & Xiaojun Chen
  7. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    • Wenxin Zheng
  8. Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    • Wenxin Zheng

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The authors declare that they have no conflict of interest.

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Correspondence to Zhenbo Zhang or Wenxin Zheng.

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https://doi.org/10.1038/s41388-018-0360-7