Cellular Oncology

, Volume 42, Issue 1, pp 55–66 | Cite as

Novel tumor suppressor SPRYD4 inhibits tumor progression in hepatocellular carcinoma by inducing apoptotic cell death

  • Kashif Rafiq Zahid
  • Shiming Han
  • Fuling Zhou
  • Umar RazaEmail author
Original Paper



Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated deaths worldwide. Although recent studies have proposed different biomarkers for HCC progression and therapy resistance, a better understanding of the molecular mechanisms underlying HCC progression and recurrence, as well as the identification of molecular markers with a higher diagnostic accuracy, are necessary for the development of more effective clinical management strategies. Here, we aimed to identify novel players in HCC progression.


SPRYD4 mRNA and protein expression analyses were carried out on a normal liver-derived cell line (HL-7702) and four HCC-derived cell lines (HepG2, SMMC7721, Huh-7, BEL-7402) using qRT-PCR and Western blotting, respectively. Cell proliferation Cell Counting Kit-8 (CCK-8) assays, protein expression analyses for apoptosis markers using Western blotting, and Caspase-Glo 3/7 apoptosis assays were carried out on the four HCC-derived cell lines. Expression comparison, functional annotation, gene set enrichment, correlation and survival analyses were carried out on patient data retrieved from the NCBI Gene module, the NCBI GEO database and the TCGA database.


Through a meta-analysis we found that the expression of SPRYD4 was downregulated in primary HCC tissues compared to non-tumor tissues. We also found that the expression of SPRYD4 was downregulated in HCC-derived cells compared to normal liver-derived cells. Subsequently, we found that the expression of SPRYD4 was inversely correlated with a gene signature associated with HCC cell proliferation. Exogenous SPRYD4 expression was found to inhibit HCC cell proliferation by inducing apoptotic cell death. We also found that SPRYD4 expression was associated with a good prognosis and that its expression became downregulated when HCCs progressed towards more aggressive stages and higher grades. Finally, we found that SPRYD4 expression may serve as a biomarker for a good overall and relapse-free survival in HCC patients.


Our data indicate that a decreased SPRYD4 expression may serve as an independent predictor for a poor prognosis in patients with HCC and that increased SPRYD4 expression may reduce HCC growth and progression through the induction of apoptotic cell death, thereby providing a potential therapeutic target.


Hepatocellular carcinoma SPRYD4 Tumor suppressor Tumor progression Apoptosis 



This work was supported in part by the Science and Technology Innovation Team Project of Liupanshui Normal University (Grant # LPSSYKJTD201602), the key disciplines of Guizhou province of China (Grant # Qian Xuewei He word ZDXK (2014)24), the Liupanshui Key Laboratory for Research and Utilization of Characteristic Fruit Tree Resources (Grant # 52020-2017-02-03) and the Research Foundation for Advanced Talents of Liupanshui Normal University (Grant # LPSSYKYJJ201601).

Compliance with ethical standards

Conflict of interest

The authors declare no potential conflicts of interest.

Supplementary material

13402_2018_407_MOESM1_ESM.pdf (12 mb)
ESM 1 (PDF 12287 kb)


  1. 1.
    US Cancer Statsitics [Internet]. N.C.I. NIH. Accessed 2 May 2018
  2. 2.
    J. Byam, J. Renz, J.M. Millis, Liver transplantation for hepatocellular carcinoma. Hepatobiliary Surg. Nutr. 2, 22–30 (2013)Google Scholar
  3. 3.
    F. Bravi, C. Bosetti, A. Tavani, S. Gallus, C. La Vecchia, Coffee reduces risk for hepatocellular carcinoma: An updated meta-analysis. Clin. Gastroenterol. Hepatol. 11 e1411, 1413–1421 (2013)Google Scholar
  4. 4.
    M.A. Gomes, D.G. Priolli, J.G. Tralhao, M.F. Botelho, Hepatocellular carcinoma: Epidemiology, biology, diagnosis, and therapies. Rev. Assoc. Med. Bras. 59, 514–524 (2013)CrossRefGoogle Scholar
  5. 5.
    A. Forner, J.M. Llovet, J. Bruix, Hepatocellular carcinoma. Lancet 379, 1245–1255 (2012)CrossRefGoogle Scholar
  6. 6.
    M. Liu, L. Jiang, X.Y. Guan, The genetic and epigenetic alterations in human hepatocellular carcinoma: A recent update. Protein Cell 5, 673–691 (2014)CrossRefGoogle Scholar
  7. 7.
    M. Morimoto, K. Numata, A. Nozaki, M. Kondo, S. Moriya, M. Taguri, S. Morita, M. Konno, A. Sugo, E. Miyajima, S. Maeda, K. Tanaka, Novel Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein: A biomarker of hepatocellular carcinoma recurrence in patients with low alpha-fetoprotein concentrations. Int. J. Clin. Oncol. 17, 373–379 (2012)CrossRefGoogle Scholar
  8. 8.
    P.M. Biselli-Chicote, A.R. Oliveira, E.C. Pavarino, E.M. Goloni-Bertollo, VEGF gene alternative splicing: Pro- and anti-angiogenic isoforms in cancer. J. Cancer Res. Clin. Oncol. 138, 363–370 (2012)CrossRefGoogle Scholar
  9. 9.
    B. Minguez, A. Lachenmayer, Diagnostic and prognostic molecular markers in hepatocellular carcinoma. Dis. Markers 31, 181–190 (2011)CrossRefGoogle Scholar
  10. 10.
    K. Schutte, C. Schulz, A. Link, P. Malfertheiner, Current biomarkers for hepatocellular carcinoma: Surveillance, diagnosis and prediction of prognosis. World J. Hepatol. 7, 139–149 (2015)CrossRefGoogle Scholar
  11. 11.
    M. Montalbano, C. Rastellini, J.T. McGuire, J. Prajapati, A. Shirafkan, R. Vento, L. Cicalese, Role of Glypican-3 in the growth, migration and invasion of primary hepatocytes isolated from patients with hepatocellular carcinoma. Cell. Oncol. 41, 169–184 (2018)CrossRefGoogle Scholar
  12. 12.
    E. Santamaria, J. Munoz, J. Fernandez-Irigoyen, J. Prieto, F.J. Corrales, Toward the discovery of new biomarkers of hepatocellular carcinoma by proteomics. Liver Int. 27, 163–173 (2007)CrossRefGoogle Scholar
  13. 13.
    R. Gopal, K. Selvarasu, P.P. Pandian, K. Ganesan, Integrative transcriptome analysis of liver cancer profiles identifies upstream regulators and clinical significance of ACSM3 gene expression. Cell. Oncol. 40, 219–233 (2017)CrossRefGoogle Scholar
  14. 14.
    V. Ramesh, K. Selvarasu, J. Pandian, S. Myilsamy, C. Shanmugasundaram, K. Ganesan, NFkappaB activation demarcates a subset of hepatocellular carcinoma patients for targeted therapy. Cell. Oncol. 39, 523–536 (2016)CrossRefGoogle Scholar
  15. 15.
    C. Ponting, J. Schultz, P. Bork, SPRY domains in ryanodine receptors (ca(2+)-release channels). Trends Biochem. Sci. 22, 193–194 (1997)CrossRefGoogle Scholar
  16. 16.
    S.L. Masters, S. Yao, T.A. Willson, J.G. Zhang, K.R. Palmer, B.J. Smith, J.J. Babon, N.A. Nicola, R.S. Norton, S.E. Nicholson, The SPRY domain of SSB-2 adopts a novel fold that presents conserved Par-4-binding residues. Nat. Struct. Mol. Biol. 13, 77–84 (2006)CrossRefGoogle Scholar
  17. 17.
    Z. Zhong, H. Zhang, M. Bai, J. Ni, B. Wan, X. Chen, L. Yu, Cloning and characterization of a novel human SPRYD4 gene encoding a putative SPRY domain-containing protein. DNA Seq. 19, 68–72 (2008)CrossRefGoogle Scholar
  18. 18.
    U. Raza, O. Saatci, S. Uhlmann, S.A. Ansari, E. Eyupoglu, E. Yurdusev, M. Mutlu, P.G. Ersan, M.K. Altundag, J.D. Zhang, H.T. Dogan, G. Guler, O. Sahin, The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer. Oncotarget 7, 49859–49877 (2016)Google Scholar
  19. 19.
    M. Mutlu, O. Saatci, S.A. Ansari, E. Yurdusev, H. Shehwana, O. Konu, U. Raza, O. Sahin, miR-564 acts as a dual inhibitor of PI3K and MAPK signaling networks and inhibits proliferation and invasion in breast cancer. Sci. Rep. 6(32541) (2016)Google Scholar
  20. 20.
    J. Chaisaingmongkol, A Budhu, H Dang, S Rabibhadana, B Pupacdi, SM Kwon, M Forgues, Y Pomyen, V Bhudhisawasdi, N Lertprasertsuke, A Chotirosniramit, C Pairojkul, CU Auewarakul, T Sricharunrat, K Phornphutkul, S Sangrajrang, M Cam, P He, SM Hewitt, K Ylaya, X Wu, JB Andersen, SS Thorgeirsson, JJ Waterfall, YJ Zhu, J Walling, HS Stevenson, D Edelman, PS Meltzer, CA Loffredo, N Hama, T Shibata, RH Wiltrout, CC Harris, C Mahidol, M Ruchirawat, XW Wang and T-L Consortium, Common molecular subtypes among Asian hepatocellular carcinoma and cholangiocarcinoma Cancer Cell 32, 57–70 e53 (2017)Google Scholar
  21. 21.
    O.V. Grinchuk, S.P. Yenamandra, R. Iyer, M. Singh, H.K. Lee, K.H. Lim, P.K. Chow, V.A. Kuznetsov, Tumor-adjacent tissue co-expression profile analysis reveals pro-oncogenic ribosomal gene signature for prognosis of resectable hepatocellular carcinoma. Mol. Oncol. 12, 89–113 (2018)CrossRefGoogle Scholar
  22. 22.
    H. Wang, X. Huo, X.R. Yang, J. He, L. Cheng, N. Wang, X. Deng, H. Jin, N. Wang, C. Wang, F. Zhao, J. Fang, M. Yao, J. Fan, W. Qin, STAT3-mediated upregulation of lncRNA HOXD-AS1 as a ceRNA facilitates liver cancer metastasis by regulating SOX4. Mol. Cancer 16(136), 136 (2017)CrossRefGoogle Scholar
  23. 23.
    Y. Hoshida, A. Villanueva, A. Sangiovanni, M. Sole, C. Hur, K.L. Andersson, R.T. Chung, J. Gould, K. Kojima, S. Gupta, B. Taylor, A. Crenshaw, S. Gabriel, B. Minguez, M. Iavarone, S.L. Friedman, M. Colombo, J.M. Llovet, T.R. Golub, Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. Gastroenterology 144, 1024–1030 (2013)CrossRefGoogle Scholar
  24. 24.
    F. Reynier, F. Petit, M. Paye, F. Turrel-Davin, P.E. Imbert, A. Hot, B. Mougin, P. Miossec, Importance of correlation between gene expression levels: Application to the type I interferon signature in rheumatoid arthritis. PLoS One 6, e24828 (2011)CrossRefGoogle Scholar
  25. 25.
    R. Satow, M. Shitashige, Y. Kanai, F. Takeshita, H. Ojima, T. Jigami, K. Honda, T. Kosuge, T. Ochiya, S. Hirohashi, T. Yamada, Combined functional genome survey of therapeutic targets for hepatocellular carcinoma. Clin. Cancer Res. 16, 2518–2528 (2010)CrossRefGoogle Scholar
  26. 26.
    C. Desmedt, A. Di Leo, E. de Azambuja, D. Larsimont, B. Haibe-Kains, J. Selleslags, S. Delaloge, C. Duhem, J.P. Kains, B. Carly, M. Maerevoet, A. Vindevoghel, G. Rouas, F. Lallemand, V. Durbecq, F. Cardoso, R. Salgado, R. Rovere, G. Bontempi, S. Michiels, M. Buyse, J.M. Nogaret, Y. Qi, F. Symmans, L. Pusztai, V. D'Hondt, M. Piccart-Gebhart, C. Sotiriou, Multifactorial approach to predicting resistance to anthracyclines. J. Clin. Oncol. 29, 1578–1586 (2011)CrossRefGoogle Scholar
  27. 27.
    M. Tsuchiya, J.S. Parker, H. Kono, M. Matsuda, H. Fujii, I. Rusyn, Gene expression in nontumoral liver tissue and recurrence-free survival in hepatitis C virus-positive hepatocellular carcinoma. Mol. Cancer 9, 74 (2010)CrossRefGoogle Scholar
  28. 28.
    B. Minguez, Y. Hoshida, A. Villanueva, S. Toffanin, L. Cabellos, S. Thung, J. Mandeli, D. Sia, C. April, J.B. Fan, A. Lachenmayer, R. Savic, S. Roayaie, V. Mazzaferro, J. Bruix, M. Schwartz, S.L. Friedman, J.M. Llovet, Gene-expression signature of vascular invasion in hepatocellular carcinoma. J. Hepatol. 55, 1325–1331 (2011)CrossRefGoogle Scholar
  29. 29.
    E.K. Tung, C.K. Mak, S. Fatima, R.C. Lo, H. Zhao, C. Zhang, H. Dai, R.T. Poon, M.F. Yuen, C.L. Lai, J.J. Li, J.M. Luk, I.O. Ng, Clinicopathological and prognostic significance of serum and tissue Dickkopf-1 levels in human hepatocellular carcinoma. Liver Int. 31, 1494–1504 (2011)CrossRefGoogle Scholar
  30. 30.
    B. Stefanska, J. Huang, B. Bhattacharyya, M. Suderman, M. Hallett, Z.G. Han, M. Szyf, Definition of the landscape of promoter DNA hypomethylation in liver cancer. Cancer Res. 71, 5891–5903 (2011)CrossRefGoogle Scholar
  31. 31.
    H.Y. Lim, I. Sohn, S. Deng, J. Lee, S.H. Jung, M. Mao, J. Xu, K. Wang, S. Shi, J.W. Joh, Y.L. Choi, C.K. Park, Prediction of disease-free survival in hepatocellular carcinoma by gene expression profiling. Ann. Surg. Oncol. 20, 3747–3753 (2013)CrossRefGoogle Scholar
  32. 32.
    J.H. Kim, B.H. Sohn, H.S. Lee, S.B. Kim, J.E. Yoo, Y.Y. Park, W. Jeong, S.S. Lee, E.S. Park, A. Kaseb, B.H. Kim, W.B. Kim, J.E. Yeon, K.S. Byun, I.S. Chu, S.S. Kim, X.W. Wang, S.S. Thorgeirsson, J.M. Luk, K.J. Kang, J. Heo, Y.N. Park, J.S. Lee, Genomic predictors for recurrence patterns of hepatocellular carcinoma: Model derivation and validation. PLoS Med. 11, e1001770 (2014)CrossRefGoogle Scholar
  33. 33.
    R.A. Busuttil, J. George, R.W. Tothill, K. Ioculano, A. Kowalczyk, C. Mitchell, S. Lade, P. Tan, I. Haviv, A. Boussioutas, A signature predicting poor prognosis in gastric and ovarian cancer represents a coordinated macrophage and stromal response. Clin. Cancer Res. 20, 2761–2772 (2014)CrossRefGoogle Scholar
  34. 34.
    E. Villa, R. Critelli, B. Lei, G. Marzocchi, C. Camma, G. Giannelli, P. Pontisso, G. Cabibbo, M. Enea, S. Colopi, C. Caporali, T. Pollicino, F. Milosa, A. Karampatou, P. Todesca, E. Bertolini, L. Maccio, M.L. Martinez-Chantar, E. Turola, M. Del Buono, N. De Maria, S. Ballestri, F. Schepis, P. Loria, G. Enrico Gerunda, L. Losi, U. Cillo, Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study. Gut 65, 861–869 (2016)CrossRefGoogle Scholar
  35. 35.
    M. Melis, G. Diaz, D.E. Kleiner, F. Zamboni, J. Kabat, J. Lai, G. Mogavero, A. Tice, R.E. Engle, S. Becker, C.R. Brown, J.C. Hanson, J. Rodriguez-Canales, M. Emmert-Buck, S. Govindarajan, M. Kew, P. Farci, Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus-associated hepatocellular carcinoma. J. Transl. Med. 12, 230 (2014)CrossRefGoogle Scholar
  36. 36.
    Y. Murakami, S. Kubo, A. Tamori, S. Itami, E. Kawamura, K. Iwaisako, K. Ikeda, N. Kawada, T. Ochiya, Y.H. Taguchi, Comprehensive analysis of transcriptome and metabolome analysis in intrahepatic cholangiocarcinoma and hepatocellular carcinoma. Sci. Rep. 5, 16294 (2015)Google Scholar
  37. 37.
    W.C. Mah, T. Thurnherr, P.K. Chow, A.Y. Chung, L.L. Ooi, H.C. Toh, B.T. Teh, Y. Saunthararajah, C.G. Lee, Methylation profiles reveal distinct subgroup of hepatocellular carcinoma patients with poor prognosis. PLoS One 9, e104158 (2014)CrossRefGoogle Scholar
  38. 38.
    K. Schulze, S. Imbeaud, E. Letouze, L.B. Alexandrov, J. Calderaro, S. Rebouissou, G. Couchy, C. Meiller, J. Shinde, F. Soysouvanh, A.L. Calatayud, R. Pinyol, L. Pelletier, C. Balabaud, A. Laurent, J.F. Blanc, V. Mazzaferro, F. Calvo, A. Villanueva, J.C. Nault, P. Bioulac-Sage, M.R. Stratton, J.M. Llovet, J. Zucman-Rossi, Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 47, 505–511 (2015)CrossRefGoogle Scholar
  39. 39.
    O. Miltiadous, D. Sia, Y. Hoshida, M.I. Fiel, A.N. Harrington, S.N. Thung, P.S. Tan, H. Dong, K. Revill, C.Y. Chang, S. Roayaie, T.J. Byrne, V. Mazzaferro, J. Rakela, S. Florman, M. Schwartz, J.M. Llovet, Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation. J. Hepatol. 63, 1368–1377 (2015)CrossRefGoogle Scholar
  40. 40.
    K.M. Lisowska, M. Olbryt, V. Dudaladava, J. Pamula-Pilat, K. Kujawa, E. Grzybowska, M. Jarzab, S. Student, I.K. Rzepecka, B. Jarzab, J. Kupryjanczyk, Gene expression analysis in ovarian cancer - faults and hints from DNA microarray study. Front. Oncol. 4, 6 (2014)Google Scholar
  41. 41.
    F. Foerster, M. Hess, A. Gerhold-Ay, J.U. Marquardt, D. Becker, P.R. Galle, D. Schuppan, H. Binder, E. Bockamp, The immune contexture of hepatocellular carcinoma predicts clinical outcome. Sci. Rep. 8, 5351 (2018)CrossRefGoogle Scholar
  42. 42.
    H.G. Woo, J.H. Choi, S. Yoon, B.A. Jee, E.J. Cho, J.H. Lee, S.J. Yu, J.H. Yoon, N.J. Yi, K.W. Lee, K.S. Suh, Y.J. Kim, Integrative analysis of genomic and epigenomic regulation of the transcriptome in liver cancer. Nat. Commun. 8, 839 (2017)CrossRefGoogle Scholar
  43. 43.
    G.M. Dancik, D. Theodorescu, Robust prognostic gene expression signatures in bladder cancer and lung adenocarcinoma depend on cell cycle related genes. PLoS One 9, e85249 (2014)CrossRefGoogle Scholar
  44. 44.
    S. Udali, P. Guarini, A. Ruzzenente, A. Ferrarini, A. Guglielmi, V. Lotto, P. Tononi, P. Pattini, S. Moruzzi, T. Campagnaro, S. Conci, O. Olivieri, R. Corrocher, M. Delledonne, S.W. Choi, S. Friso, DNA methylation and gene expression profiles show novel regulatory pathways in hepatocellular carcinoma. Clin. Epigenetics 7, 43 (2015)CrossRefGoogle Scholar
  45. 45.
    M. Grinberg, R.M. Stober, K. Edlund, E. Rempel, P. Godoy, R. Reif, A. Widera, K. Madjar, W. Schmidt-Heck, R. Marchan, A. Sachinidis, D. Spitkovsky, J. Hescheler, H. Carmo, M.D. Arbo, B. van de Water, S. Wink, M. Vinken, V. Rogiers, S. Escher, B. Hardy, D. Mitic, G. Myatt, T. Waldmann, A. Mardinoglu, G. Damm, D. Seehofer, A. Nussler, T.S. Weiss, A. Oberemm, A. Lampen, M.M. Schaap, M. Luijten, H. van Steeg, W.E. Thasler, J.C. Kleinjans, R.H. Stierum, M. Leist, J. Rahnenfuhrer, J.G. Hengstler, Toxicogenomics directory of chemically exposed human hepatocytes. Arch. Toxicol. 88, 2261–2287 (2014)CrossRefGoogle Scholar
  46. 46.
    M. Kinoshita, M. Miyata, Underexpression of mRNA in human hepatocellular carcinoma focusing on eight loci. Hepatology 36, 433–438 (2002)CrossRefGoogle Scholar
  47. 47.
    R. Tsunedomi, Y. Ogawa, N. Iizuka, K. Sakamoto, T. Tamesa, T. Moribe, M. Oka, The assessment of methylated BASP1 and SRD5A2 levels in the detection of early hepatocellular carcinoma. Int. J. Oncol. 36, 205–212 (2010)Google Scholar
  48. 48.
    H. Sun, J. Song, C. Weng, J. Xu, M. Huang, Q. Huang, R. Sun, W. Xiao, C. Sun, Association of decreased expression of the macrophage scavenger receptor MARCO with tumor progression and poor prognosis in human hepatocellular carcinoma. J. Gastroenterol. Hepatol. 32, 1107–1114 (2017)CrossRefGoogle Scholar
  49. 49.
    X. Hang, Z. Wu, K. Chu, G. Yu, H. Peng, H. Xin, X. Miao, J. Wang, W. Xu, Low expression of DCXR protein indicates a poor prognosis for hepatocellular carcinoma patients. Tumour Biol. 37, 15079–15085 (2016)CrossRefGoogle Scholar
  50. 50.
    S. Boyault, D.S. Rickman, A. de Reynies, C. Balabaud, S. Rebouissou, E. Jeannot, A. Herault, J. Saric, J. Belghiti, D. Franco, P. Bioulac-Sage, P. Laurent-Puig, J. Zucman-Rossi, Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 45, 42–52 (2007)CrossRefGoogle Scholar
  51. 51.
    C.H. Hsieh, C.K. Wei, W.Y. Yin, C.M. Chang, S.J. Tsai, L.Y. Wang, W.Y. Chiou, M.S. Lee, H.Y. Lin, S.K. Hung, Vascular invasion affects survival in early hepatocellular carcinoma. Mol. Clin. Oncol. 3, 252–256 (2015)CrossRefGoogle Scholar
  52. 52.
    L. Yang, M. Karin, Roles of tumor suppressors in regulating tumor-associated inflammation. Cell Death Differ. 21, 1677–1686 (2014)CrossRefGoogle Scholar
  53. 53.
    G.I. Evan, K.H. Vousden, Proliferation, cell cycle and apoptosis in cancer. Nature 411, 342–348 (2001)CrossRefGoogle Scholar
  54. 54.
    L.Y. Chuang, C.S. Yang, K.C. Wu, C.H. Yang, Correlation-based gene selection and classification using Taguchi-BPSO. Methods Inf. Med. 49, 254–268 (2010)CrossRefGoogle Scholar
  55. 55.
    Y. Piao, M. Piao, K. Park, K.H. Ryu, An ensemble correlation-based gene selection algorithm for cancer classification with gene expression data. Bioinformatics 28, 3306–3315 (2012)CrossRefGoogle Scholar
  56. 56.
    Z. Mousavian, A. Nowzari-Dalini, R.W. Stam, Y. Rahmatallah, A. Masoudi-Nejad, Network-based expression analysis reveals key genes related to glucocorticoid resistance in infant acute lymphoblastic leukemia. Cell. Oncol. 40, 33–45 (2017)CrossRefGoogle Scholar
  57. 57.
    M. Giulietti, G. Occhipinti, G. Principato, F. Piva, Identification of candidate miRNA biomarkers for pancreatic ductal adenocarcinoma by weighted gene co-expression network analysis. Cell. Oncol. 40, 181–192 (2017)CrossRefGoogle Scholar
  58. 58.
    M.A. El-Fattah, M. Aboelmagd, M. Elhamouly, Prognostic factors of hepatocellular carcinoma survival after radiofrequency ablation: A US population-based study. United European Gastroenterol. J. 5, 227–235 (2017)CrossRefGoogle Scholar
  59. 59.
    P.J. Thuluvath, Vascular invasion is the most important predictor of survival in HCC, but how do we find it? J. Clin. Gastroenterol. 43, 101–102 (2009)CrossRefGoogle Scholar

Copyright information

© International Society for Cellular Oncology 2018

Authors and Affiliations

  1. 1.School of Biological Sciences and TechnologyLiupanshui Normal UniversityLiupanshuiChina
  2. 2.Department of HematologyZhongnan Hospital of Wuhan UniversityWuhanChina
  3. 3.Department of Multidisciplinary StudiesNational University of Medical Sciences (NUMS)RawalpindiPakistan

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