Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Roles of PTEN (Phosphatase and Tensin Homolog) in Gastric Cancer Development and Progression

  • Xu, Wen-Ting (Department of Gastroenterology, The First Affiliated Hospital of Nanchang University) ;
  • Yang, Zhen (Department of Gastroenterology, The First Affiliated Hospital of Nanchang University) ;
  • Lu, Nong-Hua (Department of Gastroenterology, The First Affiliated Hospital of Nanchang University)
  • Published : 2014.01.15
Download PDF
⟨ Previous Next ⟩

Abstract

Gastric cancer is highly invasive, aggressively malignant, and amongst the most prevalent of all forms of cancer. Despite improved management strategies, early stage diagnosis of gastric cancer and accurate prognostic assessment is still lacking. Several recent reports have indicated that the pathogenesis of gastric cancer involves complex molecular mechanisms and multiple genetic and epigenetic alterations in oncogenes and tumor suppressor genes. Functional inactivation of the tumor suppressor protein PTEN (Phosphatase and Tensin Homolog) has been detected in multiple cases of gastric cancer, and already shown to be closely linked to the development, progression and prognosis of the disease. Inactivation of PTEN can be attributed to gene mutation, loss of heterozygosity, promoter hypermethylation, microRNA- mediated regulation of gene expression, and post-translational phosphorylation. PTEN is also involved in mechanisms regulating tumor resistance to chemotherapy. This review provides a comprehensive analysis of PTEN and its roles in gastric cancer, and emphasizes its potential benefits in early diagnosis and gene therapy-based treatment strategies.

Keywords

References

  1. Baig RM, Mahjabeen I, Sabir M, et al (2011). Genetic Changes in the PTEN Gene and their Association with Breast Cancer in Pakistan. Asian Pacific J Cancer Prev, 12, 2773-8.
  2. Bai ZG, Ye YJ, Shen DH, et al (2013). PTEN expression and suppression of proliferation are associated with Cdx2 overexpression in gastric cancercells. Int J Oncol, 42, 1682-91.
  3. Besson A, Robbins SM, Yong VW(1999). PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. Eur J Biochem, 263, 605-11. https://doi.org/10.1046/j.1432-1327.1999.00542.x
  4. Byun DS, Cho K, Ryu BK, et al (2003). Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIK-3CA amplification in gastric carcinoma. Int J Cancer, 104, 318-27. https://doi.org/10.1002/ijc.10962
  5. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, et al (2013). Integrated genomic characterization of endometrial carcinoma. Nature, 497, 67-73. https://doi.org/10.1038/nature12113
  6. Carson JP, Kulik G, Weber MJ (1999). Antiapoptotic signaling in LNCaP prostate cancer cells: a survival signaling pathway independent of phosphatidylinositol 3'-kinase and Akt/protein kinase B. Cancer Res, 59, 1449-53.
  7. Chang JG, Chen YJ, Perng LI, et al (1999). Mutation analysis of the PTEN/MMAC1 gene in cancers of the digestive tract. Eur J Cancer, 35, 647-51. https://doi.org/10.1016/S0959-8049(98)00411-0
  8. Cheung HH, Davis AJ, Lee TL, et al (2011). Methylation of an intronic region regulates miR-199a in testicular tumor malignancy. Oncogene, 30, 3404-15. https://doi.org/10.1038/onc.2011.60
  9. Chong ML, Loh M, Thakkar B, et al (2013). Phosphatidylinositol-3-kinase pathway aberrations in gastric and colorectal cancer: Meta-analysis, co-occurrence and ethnic variation. Int J Cancer, 134, 1232-8.
  10. Chun-Zhi Z, Lei H, An-Ling Z, et al (2010). MicroRNA-221 and microRNA-222 regulate gastric carcinoma cell proliferation and radioresistance by targeting PTEN. BMC Cancer, 10, 367. https://doi.org/10.1186/1471-2407-10-367
  11. Ciuffreda L, Di Sanza C, Cesta Incani U, et al (2012). The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms. J Mol Med (Berl), 90, 667-79. https://doi.org/10.1007/s00109-011-0844-1
  12. Cox G, O'Byrne KJ (2001). Matrix metalloproteinases and cancer. Anticancer Res, 21, 4207-19.
  13. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA(1995). Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature, 378, 785-9. https://doi.org/10.1038/378785a0
  14. Datta SR, Dudek H, Tao X, et al (1997). Akt phosphorylation of Bad couples survival Signals to the cell-intrinsic death machinery. Cell, 91, 231-41. https://doi.org/10.1016/S0092-8674(00)80405-5
  15. Deng N, Goh LK, Wang H, et al (2012). A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut, 61, 673-84. https://doi.org/10.1136/gutjnl-2011-301839
  16. Diehl JA, Cheng M, Roussel MF, Sherr CJ (1998). Gl ycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular lvocalization. Genes & Development, 12, 3499-511. https://doi.org/10.1101/gad.12.22.3499
  17. Esteva FJ, Guo H, Zhang S, et al. PTEN, PIK3CA, p-AKT, and p-p70S6K status: association with trastuzumab responseand survival in patients with HER2-positive metastatic breast cancer. Am J Pathol, 177, 1647-56.
  18. Gericke A, Munson M, Ross AH (2006). Regulation of the PTEN phosphatase. Gene, 374, 1-9. https://doi.org/10.1016/j.gene.2006.02.024
  19. Guggenheim DE, Shah MA (2013). Gastric cancer epidemiology and risk factors. J Surg Oncol, 107, 230-6. https://doi.org/10.1002/jso.23262
  20. Gu J, Tamura M, Yamada KM (1998). Tumor Suppressor PTEN inhibits integrin-and Growth factor-mediated mitogenactivated protein (MAP) kinase signaling pathways. J Cell Biol, 143, 1375-83. https://doi.org/10.1083/jcb.143.5.1375
  21. Guo J, Miao Y, Xiao B, et al (2009). Differential expression of microRNA species in human gastric cancer versus nontumorous Tissues. J Gastroenterol Hepatol, 24, 652-7. https://doi.org/10.1111/j.1440-1746.2008.05666.x
  22. Gyenge M, Amagase K, Kunimi S, Matsuoka R, Takeuchi K (2013). Roles of pro-angiogenic and anti-angiogenic factors as well as matrix metalloproteinases in healing of NSAIDinduced small intestinal ulcers in rats. Life Sci, 93, 441-7. https://doi.org/10.1016/j.lfs.2013.07.021
  23. Hang Y, Zheng YC, Cao Y, Li QS, Sui YJ (2005). Suppression of gastric cancer growth by adenovirus-mediated transfer of the PTEN gene. World J Gastroenterol, 11, 2224-9. https://doi.org/10.3748/wjg.v11.i15.2224
  24. He RF, Hu ZL, Wen JF (2007). Biological implication of PTEN gene expression in human gastric cancer and related molecular mechanisms. Zhonghua Binglixue Zazhi, 36, 324-8.
  25. Hino R, Uozaki H, Murakami N, et al (2009). Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. Cancer Res, 69, 2766-74. https://doi.org/10.1158/0008-5472.CAN-08-3070
  26. Hobert O (2008). Gene regulation by transcription factors and microRNAs. Science, 319, 1785-6. https://doi.org/10.1126/science.1151651
  27. Huang J, Kontos CD (2002). PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects. J Biol Chem, 277, 10760-6. https://doi.org/10.1074/jbc.M110219200
  28. Hwang PH, Kim SY, Lee JC, et al (2005). PTEN/MMAC1 enhances the growth inhibition by anticancer drugs with downregulation of IGF-II expression in gastric cancer cells. Exp Mol Med, 37, 391-8. https://doi.org/10.1038/emm.2005.49
  29. Hwang PH, Yi HK, Kim DS, et al (2001). Suppression of tumorigenicity and metastasis in B16F10 cells by PTEN/ MMAC1/TEP1 gene. Cancer Lett, 172, 83-91. https://doi.org/10.1016/S0304-3835(01)00632-2
  30. Jemal A, Bray F, Center MM, et al (2011). Global cancer Statistics. CA Cancer J Clin, 61, 69-90. https://doi.org/10.3322/caac.20107
  31. Kang YH, Lee HS, Kim WH (2002). Promoter methylation and silencing of PTEN in gastric carcinoma. Lab Invest, 82, 285-91. https://doi.org/10.1038/labinvest.3780422
  32. Kim JH, Kang JW, Kim MS, et al (2012). The apoptotic effects of the flavonoid N101-2 in human cervical cancer cells. Toxicol In Vitro, 26, 67-73. https://doi.org/10.1016/j.tiv.2011.10.012
  33. Kim JS, Xu X, Li H, et al (2011). Mechanistic analysis of a DNA damage-induced, PTEN-dependent size checkpoint in human cells. Mol Cell Biol, 31, 2756-71. https://doi.org/10.1128/MCB.01323-10
  34. Kim TS, Kim YB (1999). Correlation between expression of matrix metalloproteinas-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) and angiogenesis in colorectal adenocarcinoma. J Korean Med Sci, 14, 263-70. https://doi.org/10.3346/jkms.1999.14.3.263
  35. Krajewska M, Wang HG, Krajewski S, et al (1997). Immunohistochemical analysis of in vivo patterns of expression of CPP32 (Caspase-3), a cell death protease. Cancer Res, 57, 1605-13.
  36. Lau MT, Klausen C, Leung PC(2011). E-cadherin inhibits tumor cell growth by suppressing PI3K/Akt signaling via b-catenin-Egr1-mediated PTEN expression. Oncogene, 30, 2753-66. https://doi.org/10.1038/onc.2011.6
  37. Lee Jr JT, Steelman LS, McCubrey JA (2004). Phosphatidylinositol 3?-kinase activation leads to multidrug resistance protein-1 expression and subsequent chemoresi-stance in advanced prostate cancer cells. Cancer Res, 64, 8397-404. https://doi.org/10.1158/0008-5472.CAN-04-1612
  38. Li DM, Sun H(1997). TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res, 57, 2124-9.
  39. Li J, Yen C, Liaw D, et al (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science, 275, 1943-7. https://doi.org/10.1126/science.275.5308.1943
  40. Lima EM, Araujo JJ, Harada ML,et al (2005). Molecular study of the tumour suppressor gene PTEN in gastric adenocarcinoma in Brazil. Clin Exp Med, 5, 129-32. https://doi.org/10.1007/s10238-005-0077-0
  41. Li M, Sun H, Song L, et al (2012). Immunohistochemical expression of mTOR negatively correlates with PTEN expression in gastric carcinoma. Oncol Lett, 4,1213-8.
  42. Li Y, Cui J, Zhang CH, et al (2013). High-expression of DJ-1 and loss of PTEN associated with tumor metastasis and correlated with poor prognosis of gastric carcinoma. Int J Med Sci, 10, 1689-97. https://doi.org/10.7150/ijms.7292
  43. Li YL, Tian Z, Wu DY, Fu BY, Xin Y (2005). Loss of heterozygosity on 10q23.3 and mutation of tumor suppressor gene PTEN in gastric cancer and precancerous lesions. World J Gastroenterol, 11, 285-8. https://doi.org/10.3748/wjg.v11.i2.285
  44. Maehama T, Dixon JE (1998). The tumor suppressor, PTEN/ MMAC1, dephosphorylates the lipid Second messenger, phosphatidylinositol 3, 4, 5-trisphosphate. J Biol Chem, 273, 13375-8. https://doi.org/10.1074/jbc.273.22.13375
  45. Maehama T, Taylor GS, Dixon JE (2001). PTEN and myotubularin: novel phosphoinositide phosphatases. Annu Rev Biochem, 70, 247-79. https://doi.org/10.1146/annurev.biochem.70.1.247
  46. Martelli AM, Evangelisti C, Chappell W, et al (2011). Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR Pathway. Leukemia, 25,1064-79. https://doi.org/10.1038/leu.2011.46
  47. Meng X, Wang Y, Zheng X, et al (2012). ShRNA-mediated knockdown of Bmi-1 inhibit lung adenocarcinoma cell migration and Metastasis. Lung Cancer, 77, 24-30. https://doi.org/10.1016/j.lungcan.2012.02.015
  48. Moon SH, Kim DK, Cha Y, et al (2013). PI3K/Akt and Stat3 signaling regulated by PTEN control of the cancer stem cell population, proliferation and senescence in a glioblastoma cell line. Int J Oncol, 42, 921-8.
  49. Oki E, Baba H, Tokunaga E, et al (2005). Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer, 117, 376-80. https://doi.org/10.1002/ijc.21170
  50. Oki E, Kakeji Y, Baba H, et al (2006). Impact of loss of heterozygosity of encoding phosphate and tensin homolog on the prognosis of gastric cancer. J Gastroenterol Hepatol, 21, 814-8. https://doi.org/10.1111/j.1440-1746.2005.04028.x
  51. Patel L, Pass I, Coxon P, et al (2001). Tumor suppressor and antiinflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr Biol, 11,764-8. https://doi.org/10.1016/S0960-9822(01)00225-1
  52. Patel R, Gao M, Ahmad I, et al (2013). Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression. J Clin Invest, 123, 1157-75. https://doi.org/10.1172/JCI63672
  53. Rahdar M, Inoue T, Meyer T, et al (2009). phosphorylationdependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. ProcNatl Acad Sci USA, 106, 480-5. https://doi.org/10.1073/pnas.0811212106
  54. Romano C, Schepis C (2012). PTEN gene: a model for genetic diseases in dermatology. Sci World J, 2012, 252457.
  55. Sakamaki J, Daitoku H, Ueno K, et al (2011). Arginine methylation of BCL-2 antagonist of cell death (BAD) counteracts its phosphorylation and inactivation by Akt. Proc Natl Acad Sci USA, 108, 6085-90. https://doi.org/10.1073/pnas.1015328108
  56. Sato K, Tamura G, Tsuchiya T, et al (2002). Analysis of genetic and epigenetic alterations of the PTEN gene in gastric cancer. Virchows Arch, 440,160-5. https://doi.org/10.1007/s004280100499
  57. Schoof CR, Botelho EL, Izzotti A, dos Vasques LR (2012). MicroRNAs in cancer treatment and prognosis. Am J Cancer Res, 2, 414-33.
  58. Schwartzbauer G, Robbins J (2001). The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival. J Biol Chem, 276, 35786-93. https://doi.org/10.1074/jbc.M102479200
  59. Shen WH, Balajee AS, Wang J, et al (2007). Essential role for nuclear PTEN in Maintaining chromosomal integrity. Cell, 128, 157-70. https://doi.org/10.1016/j.cell.2006.11.042
  60. Song MS, Carracedo A, Salmena L, et al (2011). Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner. Cell, 144, 187-99. https://doi.org/10.1016/j.cell.2010.12.020
  61. Stambolic V, MacPherson D, Sas D, et al (2001). Regulation of PTEN transcription by p53. Mol Cell, 8, 317-25. https://doi.org/10.1016/S1097-2765(01)00323-9
  62. Steck PA, Pershouse MA, Jasser SA, et al (1997). Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet, 15, 356-62. https://doi.org/10.1038/ng0497-356
  63. Tamguney T, Stokoe D (2007). New insights into PTEN. J Cell Sci, 120, 4071-9. https://doi.org/10.1242/jcs.015230
  64. Tamura M, Gu J, Matsumoto K, et al (1998). Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science, 280, 1614-7. https://doi.org/10.1126/science.280.5369.1614
  65. Tamura M, Gu J, Takino T, Yamada KM (1999). Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. Cancer Res, 59, 442-9.
  66. Tian L, Fang YX, Xue JL, Chen JZ (2013). Four microRNAs promote prostate cell proliferation with regulation of PTEN and its downstream signals in vitro. PLoS One, 8, e75885. https://doi.org/10.1371/journal.pone.0075885
  67. Torres J, Pulido R (2001). The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation. J Biol Chem, 276, 993-8. https://doi.org/10.1074/jbc.M009134200
  68. Trotman LC, Wang X, Alimonti A, et al (2007). Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell, 128, 141-56. https://doi.org/10.1016/j.cell.2006.11.040
  69. Vazquez F, Ramaswamy S, Nakamura N, Sellers WR (2000). Phosphory-lation of the PTEN tail regulates protein stability and function. Mol Cell Biol, 20, 5010-8. https://doi.org/10.1128/MCB.20.14.5010-5018.2000
  70. Virolle T, Adamson ED, Baron V, et al (2001). The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling. Nat Cell Biol, 3, 1124-8. https://doi.org/10.1038/ncb1201-1124
  71. Wagner AD, Unverzagt S, Grothe W, et al (2010). Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev, 3, CD004064.
  72. Waite KA, Eng C (2002). Protean PTEN: form and function. Am J Hum Genet, 70, 829-44. https://doi.org/10.1086/340026
  73. Wang JY, Huang TJ, Chen FM, et al (2003). Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in advanced gastric carcinomas. Virchows Arch, 442, 437-43.
  74. Wang X, Trotman LC, Koppie T, et al (2007). NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell, 128, 129-39. https://doi.org/10.1016/j.cell.2006.11.039
  75. Wang ZX, Lu BB, Wang H, Cheng ZX, Yin YMM (2011). MicroRNA-21 modulates chemosensitivity of breast cancer cells to doxorubicin by targeting PTEN. Arch Med Res, 42, 281-90. https://doi.org/10.1016/j.arcmed.2011.06.008
  76. Wick W, Furnari FB, Naumann U, Cavenee WK, Weller M (1999). PTEN genetransfer in human malignant glioma: sensitization to irradiation and CD95L-induced apoptosis. Oncogene, 18, 3936-43. https://doi.org/10.1038/sj.onc.1202774
  77. Xu JL, Wang ZW, Hu LM, et al (2012). Genetic Variants in the PI3K/PTEN/AKT/mTOR Pathway Predict Platinum-based Chemotherapy Response of Advanced Non-small Cell Lung Cancers in a Chinese Population. Asian Pacific J Cancer Prev, 13, 2157-62. https://doi.org/10.7314/APJCP.2012.13.5.2157
  78. Yang E, Zha J, Jockel J, et al (1995). Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell, 80, 285-91. https://doi.org/10.1016/0092-8674(95)90411-5
  79. Yang L, Kuang LG, Zheng HC, et al (2003). PTEN encoding product: a marker for tumorigenesis and progression of gastric carcinoma. World J Gastroenterol, 9, 35-9.
  80. Yang TS, Yang XH, Wang XD, et al (2013). MiR-214 regulate gastric cancer cell proliferation, migration and invasion by targeting PTEN. Cancer Cell Int, 13, 68. https://doi.org/10.1186/1475-2867-13-68
  81. Yang Z, Yuan XG, Chen J, Lu NH (2012). Is NEDD4-1 a negative regulator of phosphatase and tensin homolog in gastric carcinogenesis? World J Gastroenterol, 18, 6345-8. https://doi.org/10.3748/wjg.v18.i43.6345
  82. Yang Z, Yuan XG, Chen J, et al (2013). Reduced expression of PTEN and increased PTEN phosphorylation at residue Ser380 in gastric cancer tissues: a novel mechanism of PTEN inactivation. Clin Res Hepatol Gastroenterol, 37, 72-9. https://doi.org/10.1016/j.clinre.2012.03.002
  83. Ye B, Jiang LL, Xu HT, Zhou DW, Li ZS (2012). Expression of PI3K/AKT pathway in gastric cancer and its blockade suppresses tumor growth and metastasis. Int J Immunopathol Pharmacol, 25, 627-36.
  84. Yu BQ, Su LP, Li JF, et al (2012). microRNA expression signature of gastric cancer cells relative to normal gastric mucosa. Mol Med Rep, 6, 821-6.
  85. Yu HG, Ai YW, Yu LL, et al (2008). Phosphoinositide 3-kinase/ Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death. Int J Cancer, 122, 433-43. https://doi.org/10.1002/ijc.23049
  86. Zhang S, Huang WC, Li P, et al (2011). Combating trastuzmab resistance by targeting SRC, a common node down-stream of multiple resistance pathways. Nat Med, 17, 461-9. https://doi.org/10.1038/nm.2309
  87. Zhang X, Yan Z, Zhang J, et al (2011). Combination of hsamiR-375 and hsa-miR-142-5p as a predictor for recurrence risk in gastric cancer patients Following surgical resection. Ann Oncol, 22, 2257-66. https://doi.org/10.1093/annonc/mdq758
  88. Zheng HC, Chen Y, Kuang LG, et al (2003). Expression of PTEN-encoding product in different stages of carcinogenesis and progression of gastric Carcinoma. ZhonghuaZhongliu Zazhi, 25, 13-6.
  89. Zheng HC, Sun JM, Li XH, et al (2003). Role of PTEN and MMP-7 expression in growth, invasion, metastasis and angiogenesis of gastric carcinoma. Pathol Int, 53, 659-66. https://doi.org/10.1046/j.1440-1827.2003.01542.x

Cited by

  1. Phosphorylated insulin-like growth factor-1 receptor expression predicts poor prognosis of Chinese patients with gastric cancer vol.31, pp.12, 2014, https://doi.org/10.1007/s12032-014-0141-2
  2. The Role of PI3K/Akt/mTOR Signaling in Gastric Carcinoma vol.6, pp.3, 2014, https://doi.org/10.3390/cancers6031441
  3. Current clinical regulation of PI3K/PTEN/Akt/mTOR signalling in treatment of human cancer vol.141, pp.4, 2015, https://doi.org/10.1007/s00432-014-1803-3
  4. Expression of Fatty Acid Synthase Negatively Correlates with PTEN and Predicts Peritoneal Dissemination of Human Gastric Cancer vol.16, pp.16, 2015, https://doi.org/10.7314/APJCP.2015.16.16.6851
  5. Association of the PTEN IVS4 (rs3830675) Gene Polymorphism with Reduced Risk of Cancer: Evidence from a Meta-analysis vol.16, pp.3, 2015, https://doi.org/10.7314/APJCP.2015.16.3.897
  6. α-Fetoprotein-Producing Hepatoid Gastric Adenocarcinoma With Osteoclast-Like Giant Cells and Neuroendocrine Differentiation vol.23, pp.7, 2015, https://doi.org/10.1177/1066896915586807
  7. Oridonin Suppresses Proliferation of Human Ovarian Cancer Cells via Blockage of mTOR Signaling vol.17, pp.2, 2016, https://doi.org/10.7314/APJCP.2016.17.2.667
  8. Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis vol.21, pp.1, 2016, https://doi.org/10.1007/s10495-015-1188-z
  9. Inhibition of microRNA-181a may suppress proliferation and invasion and promote apoptosis of cervical cancer cells through the PTEN/Akt/FOXO1 pathway vol.72, pp.4, 2016, https://doi.org/10.1007/s13105-016-0511-7
  10. Gene mutations in stool from gastric and colorectal neoplasia patients by next-generation sequencing vol.23, pp.47, 2017, https://doi.org/10.3748/wjg.v23.i47.8291
  11. Expression of PTEN and Its Correlation with Proliferation Marker Ki-67 in Head and Neck Cancer vol.31, pp.2, 2016, https://doi.org/10.5301/jbm.5000196
  12. The crosstalk between gut microbiota and obesity and related metabolic disorders vol.11, pp.6, 2016, https://doi.org/10.2217/fmb-2015-0024
  13. Downregulation of Notch1 inhibits the invasion and metastasis of human gastric cancer cells SGC7901 and MKN74 in vitro through PTEN activation and dephosphorylation of Akt and FAK vol.16, pp.2, 2017, https://doi.org/10.3892/mmr.2017.6791
  14. Expression of Phosphoinositide 3-Kinase p110α and p110β Subunits and PIK3CA Mutation in Patients With Advanced Gastric Carcinoma pp.1541-2016, 2017, https://doi.org/10.1097/PAI.0000000000000524
  15. miR-21 and miR-19b delivered by hMSC-derived EVs regulate the apoptosis and differentiation of neurons in patients with spinal cord injury pp.00219541, 2019, https://doi.org/10.1002/jcp.27690
  16. Immunohistochemical classification of gastric cancer based on new molecular biomarkers: a potential predictor of survival pp.1432-2307, 2018, https://doi.org/10.1007/s00428-018-2443-9
  17. Baicalein inhibits cell growth and increases cisplatin sensitivity of A549 and H460 cells via miR-424-3p and targeting PTEN/PI3K/Akt pathway vol.22, pp.4, 2018, https://doi.org/10.1111/jcmm.13556
  18. CircPSMC3 suppresses the proliferation and metastasis of gastric cancer by acting as a competitive endogenous RNA through sponging miR-296-5p vol.18, pp.1, 2019, https://doi.org/10.1186/s12943-019-0958-6