Candidate biomarkers for cervical cancer treatment: Potential for clinical practice (Review)

Iida,Miho; Banno,Kouji; Yanokura,Megumi; Nakamura,Kanako; Adachi,Masataka; Nogami,Yuya; Umene,Kiyoko; Masuda,Kenta; Kisu,Iori; Iwata,Takashi; Tanaka,Kyoko; Aoki,Daisuke

doi:10.3892/mco.2014.324

Candidate biomarkers for cervical cancer treatment: Potential for clinical practice (Review)

Authors:
- Miho Iida
- Kouji Banno
- Megumi Yanokura
- Kanako Nakamura
- Masataka Adachi
- Yuya Nogami
- Kiyoko Umene
- Kenta Masuda
- Iori Kisu
- Takashi Iwata
- Kyoko Tanaka
- Daisuke Aoki
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo 160‑8582, Japan
Published online on: June 23, 2014 https://doi.org/10.3892/mco.2014.324
Pages: 647-655

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cervical cancer ranks high among the causes of female cancer mortalities and is an important disease in developing and developed countries. Current diagnosis of cervical cancer depends on colposcopy, pathological diagnosis and preoperative diagnosis using methods, including magnetic resonance imaging and computed tomography. Advanced cervical cancer has a poor prognosis. The tumor marker squamous cell carcinoma is conventionally used for screening, but recent studies have revealed the mechanisms of carcinogenesis and the factors associated with a poor prognosis in cervical cancer. These include epigenetic biomarkers, with the methylation level of the checkpoint with forkhead and ring finger gene being potentially useful for predicting the malignancy of cervical cancer and sensitivity to treatment with paclitaxel. The extent of methylation of the Werner DNA helicase gene is also useful for determining sensitivity to an anticancer agent, CPT‑11. In addition to epigenetic changes, the expression levels of hypoxia‑inducible factor 1α subunit, epidermal growth factor receptor and cyclooxygenase‑2 have been reported as possible biomarkers in cervical cancer. Novel prognostic factors, including angiogenic factors, fragile histidine triad, thymidylate synthase, glucose‑related protein 58 and mucin antigens, have also been described, and hemoglobin and platelets may also be significant prognostic biomarkers. Utilization of these biomarkers may facilitate personalized treatment and improved outcomes in cervical cancer.

View Figures

View References

1	Greenlee RT, Murray T, Bolden S and Wingo PA: Cancer statistics, 2000. CA Cancer J Clin. 50:7–33. 2000. View Article : Google Scholar
2	Ushijima K: Current status of gynecologic cancer in Japan. J Gynecol Oncol. 20:67–71. 2009. View Article : Google Scholar : PubMed/NCBI
3	Soonthornthum T, Arias-Pulido H, Joste N, et al: Epidermal growth factor receptor as a biomarker for cervical cancer. Ann Oncol. 22:2166–2178. 2011. View Article : Google Scholar : PubMed/NCBI
4	Noordhuis MG, Eijsink JJ, Ten Hoor KA, et al: Expression of epidermal growth factor receptor (EGFR) and activated EGFR predict poor response to (chemo)radiation and survival in cervical cancer. Clin Cancer Res. 15:7389–7397. 2009. View Article : Google Scholar : PubMed/NCBI
5	Gadducci A, Guerrieri ME and Greco C: Tissue biomarkers as prognostic variables of cervical cancer. Crit Rev Oncol Hematol. 86:104–129. 2013. View Article : Google Scholar : PubMed/NCBI
6	Noordhuis MG, Eijsink JJ, Roossink F, et al: Prognostic cell biological markers in cervical cancer patients primarily treated with (chemo)radiation: a systematic review. Int J Radiat Oncol Biol Phys. 79:325–334. 2011. View Article : Google Scholar : PubMed/NCBI
7	Sanbhnani S and Yeong FM: CHFR: a key checkpoint component implicated in a wide range of cancers. Cell Mol Life Sci. 69:1669–1687. 2012. View Article : Google Scholar : PubMed/NCBI
8	Banno K, Yanokura M, Kawaguchi M, et al: Epigenetic inactivation of the CHFR gene in cervical cancer contributes to sensitivity to taxanes. Int J Oncol. 31:713–720. 2007.PubMed/NCBI
9	Thigpen JT, Blessing JA, Fowler WC Jr and Hatch K: Phase II trials of cisplatin and piperazinedione as single agents in the treatment of advanced or recurrent non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study. Cancer Treat Rep. 70:1097–1100. 1986.PubMed/NCBI
10	Papadimitriou CA, Sarris K, Moulopoulos LA, et al: Phase II trial of paclitaxel and cisplatin in metastatic and recurrent carcinoma of the uterine cervix. J Clin Oncol. 17:761–766. 1999.PubMed/NCBI
11	Zhang Y, Chen FQ, Sun YH, Zhou SY, Li TY and Chen R: Effects of DNMT1 silencing on malignant phenotype and methylated gene expression in cervical cancer cells. J Exp Clin Cancer Res. 30:982011. View Article : Google Scholar : PubMed/NCBI
12	Peng DF, Kanai Y, Sawada M, et al: DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. Carcinogenesis. 27:1160–1168. 2006. View Article : Google Scholar : PubMed/NCBI
13	Liu N, Zhao LJ, Li XP, Wang JL, Chai GL and Wei LH: Histone deacetylase inhibitors inducing human cervical cancer cell apoptosis by decreasing DNA-methyltransferase 3B. Chin Med J (Engl). 125:3273–3278. 2012.PubMed/NCBI
14	Tadokoro T, Rybanska-Spaeder I, Kulikowicz T, et al: Functional deficit associated with a missense Werner syndrome mutation. DNA Repair (Amst). 12:414–421. 2013. View Article : Google Scholar : PubMed/NCBI
15	Masuda K, Banno K, Yanokura M, et al: Association of epigenetic inactivation of the WRN gene with anticancer drug sensitivity in cervical cancer cells. Oncol Rep. 28:1146–1152. 2012.PubMed/NCBI
16	Futami K, Takagi M, Shimamoto A, Sugimoto M and Furuichi Y: Increased chemotherapeutic activity of camptothecin in cancer cells by siRNA-induced silencing of WRN helicase. Biol Pharm Bull. 30:1958–1961. 2007. View Article : Google Scholar : PubMed/NCBI
17	Agrelo R, Cheng WH, Setien F, et al: Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proc Natl Acad Sci USA. 103:8822–8827. 2006. View Article : Google Scholar : PubMed/NCBI
18	Höpfl G, Ogunshola O and Gassmann M: HIFs and tumors - causes and consequences. Am J Physiol Regul Integr Comp Physiol. 286:R608–R623. 2004.PubMed/NCBI
19	Liao D and Johnson RS: Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 26:281–290. 2007. View Article : Google Scholar : PubMed/NCBI
20	Vaupel P: Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol. 14:198–206. 2004. View Article : Google Scholar : PubMed/NCBI
21	Michieli P: Hypoxia, angiogenesis and cancer therapy: to breathe or not to breathe? Cell Cycle. 8:3291–3296. 2009. View Article : Google Scholar : PubMed/NCBI
22	Sasabe E, Zhou X, Li D, Oku N, Yamamoto T and Osaki T: The involvement of hypoxia-inducible factor-1alpha in the susceptibility to gamma-rays and chemotherapeutic drugs of oral squamous cell carcinoma cells. Int J Cancer. 120:268–277. 2007. View Article : Google Scholar : PubMed/NCBI
23	Smith-McCune KK and Weidner N: Demonstration and characterization of the angiogenic properties of cervical dysplasia. Cancer Res. 54:800–804. 1994.PubMed/NCBI
24	Mazibrada J, Rittà M, Mondini M, et al: Interaction between inflammation and angiogenesis during different stages of cervical carcinogenesis. Gynecol Oncol. 108:112–120. 2008. View Article : Google Scholar : PubMed/NCBI
25	Lee WY, Huang SC, Hsu KF, Tzeng CC and Shen WL: Roles for hypoxia-regulated genes during cervical carcinogenesis: somatic evolution during the hypoxia-glycolysis-acidosis sequence. Gynecol Oncol. 108:377–384. 2008. View Article : Google Scholar
26	Hutchison GJ, Valentine HR, Loncaster JA, et al: Hypoxia-inducible factor 1alpha expression as an intrinsic marker of hypoxia: correlation with tumor oxygen, pimonidazole measurements, and outcome in locally advanced carcinoma of the cervix. Clin Cancer Res. 10:8405–8412. 2004. View Article : Google Scholar
27	Burri P, Djonov V, Aebersold DM, et al: Significant correlation of hypoxia-inducible factor-1alpha with treatment outcome in cervical cancer treated with radical radiotherapy. Int J Radiat Oncol Biol Phys. 56:494–501. 2003. View Article : Google Scholar
28	Bachtiary B, Schindl M, Pötter R, et al: Overexpression of hypoxia-inducible factor 1alpha indicates diminished response to radiotherapy and unfavorable prognosis in patients receiving radical radiotherapy for cervical cancer. Clin Cancer Res. 9:2234–2240. 2003.
29	Bai H, Ge S, Lu J, Qian G and Xu R: Hypoxia inducible factor-1α-mediated activation of survivin in cervical cancer cells. J Obstet Gynaecol Res. 39:555–563. 2013.
30	Li R, Zhou L and Liu Q: Effect of different animal skin on the transdermal speed constant of sinomenine. Zhong Yao Cai. 21:580–583. 1998.(In Chinese).
31	Luczak MW, Roszak A, Pawlik P, et al: Transcriptional analysis of CXCR4, DNMT3A, DNMT3B and DNMT1 gene expression in primary advanced uterine cervical carcinoma. Int J Oncol. 40:860–866. 2012.PubMed/NCBI
32	Kummar S, Raffeld M, Juwara L, et al: Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1α in advanced solid tumors. Clin Cancer Res. 17:5123–5131. 2011.PubMed/NCBI
33	Rapisarda A, Shoemaker RH and Melillo G: Targeting topoisomerase I to inhibit hypoxia inducible factor 1. Cell Cycle. 3:172–175. 2004. View Article : Google Scholar : PubMed/NCBI
34	Rapisarda A, Uranchimeg B, Scudiero DA, et al: Identification of small molecule inhibitors of hypoxia-inducible factor 1 transcriptional activation pathway. Cancer Res. 62:4316–4324. 2002.PubMed/NCBI
35	Rapisarda A, Uranchimeg B, Sordet O, Pommier Y, Shoemaker RH and Melillo G: Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Res. 64:1475–1482. 2004. View Article : Google Scholar : PubMed/NCBI
36	Hynes NE and Lane HA: ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 5:341–354. 2005. View Article : Google Scholar : PubMed/NCBI
37	Yarden Y and Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2:127–137. 2001. View Article : Google Scholar : PubMed/NCBI
38	Liang K, Ang KK, Milas L, Hunter N and Fan Z: The epidermal growth factor receptor mediates radioresistance. Int J Radiat Oncol Biol Phys. 57:246–254. 2003. View Article : Google Scholar : PubMed/NCBI
39	Milas L, Fan Z, Andratschke NH and Ang KK: Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int J Radiat Oncol Biol Phys. 58:966–971. 2004. View Article : Google Scholar : PubMed/NCBI
40	Halle C, Lando M, Svendsrud DH, et al: Membranous expression of ectodomain isoforms of the epidermal growth factor receptor predicts outcome after chemoradiotherapy of lymph node-negative cervical cancer. Clin Cancer Res. 17:5501–5512. 2011. View Article : Google Scholar
41	Iida K, Nakayama K, Rahman MT, et al: EGFR gene amplification is related to adverse clinical outcomes in cervical squamous cell carcinoma, making the EGFR pathway a novel therapeutic target. Br J Cancer. 105:420–427. 2011. View Article : Google Scholar : PubMed/NCBI
42	Schrevel M, Karim R, ter Haar NT, et al: CXCR7 expression is associated with disease-free and disease-specific survival in cervical cancer patients. Br J Cancer. 106:1520–1525. 2012. View Article : Google Scholar : PubMed/NCBI
43	Monk BJ, Mas Lopez L, Zarba JJ, et al: Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer. J Clin Oncol. 28:3562–3569. 2010. View Article : Google Scholar
44	Costa S, Terzano P, Bovicelli A, et al: CD44 isoform 6 (CD44v6) is a prognostic indicator of the response to neoadjuvant chemotherapy in cervical carcinoma. Gynecol Oncol. 80:67–73. 2001. View Article : Google Scholar : PubMed/NCBI
45	Chung HH, Kim MK, Kim JW, et al: XRCC1 R399Q polymorphism is associated with response to platinum-based neoadjuvant chemotherapy in bulky cervical cancer. Gynecol Oncol. 103:1031–1037. 2006. View Article : Google Scholar : PubMed/NCBI
46	Faried LS, Faried A, Kanuma T, et al: Predictive and prognostic role of activated mammalian target of rapamycin in cervical cancer treated with cisplatin-based neoadjuvant chemotherapy. Oncol Rep. 16:57–63. 2006.PubMed/NCBI
47	Gupta RA and Dubois RN: Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer. 1:11–21. 2001. View Article : Google Scholar : PubMed/NCBI
48	Zhang F, Engebretson SP, Morton RS, Cavanaugh PF Jr, Subbaramaiah K and Dannenberg AJ: The overexpression of cyclo-oxygenase-2 in chronic periodontitis. J Am Dent Assoc. 134:861–867. 2003. View Article : Google Scholar : PubMed/NCBI
49	Katori M and Majima M: Cyclooxygenase-2: its rich diversity of roles and possible application of its selective inhibitors. Inflamm Res. 49:367–392. 2000. View Article : Google Scholar : PubMed/NCBI
50	Kulkarni S, Rader JS, Zhang F, et al: Cyclooxygenase-2 is overexpressed in human cervical cancer. Clin Cancer Res. 7:429–434. 2001.PubMed/NCBI
51	Raju U, Ariga H, Dittmann K, Nakata E, Ang KK and Milas L: Inhibition of DNA repair as a mechanism of enhanced radioresponse of head and neck carcinoma cells by a selective cyclooxygenase-2 inhibitor, celecoxib. Int J Radiat Oncol Biol Phys. 63:520–528. 2005. View Article : Google Scholar : PubMed/NCBI
52	Xia S, Zhao Y, Yu S and Zhang M: Activated PI3K/Akt/COX-2 pathway induces resistance to radiation in human cervical cancer HeLa cells. Cancer Biother Radiopharm. 25:317–323. 2010. View Article : Google Scholar : PubMed/NCBI
53	Wang AH, Tian XY, Yu JJ, Mi JQ, Liu H and Wang RF: Celecoxib radiosensitizes the human cervical cancer HeLa cell line via a mechanism dependent on reduced cyclo-oxygenase-2 and vascular endothelial growth factor C expression. J Int Med Res. 40:56–66. 2012. View Article : Google Scholar
54	Ferrandina G, Ranelletti FO, Legge F, et al: Prognostic role of the ratio between cyclooxygenase-2 in tumor and stroma compartments in cervical cancer. Clin Cancer Res. 10:3117–3123. 2004. View Article : Google Scholar : PubMed/NCBI
55	Kim YB, Kim GE, Pyo HR, et al: Differential cyclooxygenase-2 expression in squamous cell carcinoma and adenocarcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys. 60:822–829. 2004. View Article : Google Scholar : PubMed/NCBI
56	Kim GE, Kim YB, Cho NH, et al: Synchronous coexpression of epidermal growth factor receptor and cyclooxygenase-2 in carcinomas of the uterine cervix: a potential predictor of poor survival. Clin Cancer Res. 10:1366–1374. 2004. View Article : Google Scholar : PubMed/NCBI
57	Suzuki M, Tsukagoshi S, Saga Y, Ohwada M and Sato I: Enhanced expression of thymidylate synthase may be of prognostic importance in advanced cervical cancer. Oncology. 57:50–54. 1999. View Article : Google Scholar : PubMed/NCBI
58	Kawanaka T, Kubo A, Ikushima H, Sano T, Takegawa Y and Nishitani H: Prognostic significance of HIF-2alpha expression on tumor infiltrating macrophages in patients with uterine cervical cancer undergoing radiotherapy. J Med Invest. 55:78–86. 2008. View Article : Google Scholar
59	Blancher C, Moore JW, Talks KL, Houlbrook S and Harris AL: Relationship of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression to vascular endothelial growth factor induction and hypoxia survival in human breast cancer cell lines. Cancer Res. 60:7106–7113. 2000.
60	Ziemer LS, Koch CJ, Maity A, Magarelli DP, Horan AM and Evans SM: Hypoxia and VEGF mRNA expression in human tumors. Neoplasia. 3:500–508. 2001. View Article : Google Scholar : PubMed/NCBI
61	Vaupel P, Kelleher DK and Höckel M: Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy. Semin Oncol. 28(Suppl 8): 29–35. 2001. View Article : Google Scholar : PubMed/NCBI
62	Girinski T, Pejovic-Lenfant MH, Bourhis J, et al: Prognostic value of hemoglobin concentrations and blood transfusions in advanced carcinoma of the cervix treated by radiation therapy: results of a retrospective study of 386 patients. Int J Radiat Oncol Biol Phys. 16:37–42. 1989. View Article : Google Scholar
63	Thomas G: The effect of hemoglobin level on radiotherapy outcomes: the Canadian experience. Semin Oncol. 28(Suppl 8): 60–65. 2001. View Article : Google Scholar : PubMed/NCBI
64	Hernandez E, Donohue KA, Anderson LL, Heller PB and Stehman FB: The significance of thrombocytosis in patients with locally advanced cervical carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 78:137–142. 2000. View Article : Google Scholar : PubMed/NCBI
65	Kato H and Torigoe T: Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma. Cancer. 40:1621–1628. 1977. View Article : Google Scholar : PubMed/NCBI
66	Kato H, Morioka H, Tsutsui H, Aramaki S and Torigoe T: Value of tumor-antigen (TA-4) of squamous cell carcinoma in predicting the extent of cervical cancer. Cancer. 50:1294–1296. 1982. View Article : Google Scholar : PubMed/NCBI
67	Maruo T, Shibata K, Kimura A, Hoshina M and Mochizuki M: Tumor-associated antigen, TA-4, in the monitoring of the effects of therapy for squamous cell carcinoma of the uterine cervix. Serial determinations and tissue localization. Cancer. 56:302–308. 1985. View Article : Google Scholar : PubMed/NCBI
68	Bolger BS, Dabbas M, Lopes A and Monaghan JM: Prognostic value of preoperative squamous cell carcinoma antigen level in patients surgically treated for cervical carcinoma. Gynecol Oncol. 65:309–313. 1997. View Article : Google Scholar : PubMed/NCBI
69	Takeshima N, Hirai Y, Katase K, Yano K, Yamauchi K and Hasumi K: The value of squamous cell carcinoma antigen as a predictor of nodal metastasis in cervical cancer. Gynecol Oncol. 68:263–266. 1998. View Article : Google Scholar : PubMed/NCBI
70	Puthucode-Easwaran S, Naik R, Athavale R, et al: Comparison of pre-treatment CYFRA 21–1 and SCC-Antigen assay in primary cervical carcinoma - a preliminary report. J Obstet Gynaecol. 25:486–488. 2005.
71	Duk JM, de Bruijn HW, Groenier KH, et al: Cancer of the uterine cervix: sensitivity and specificity of serum squamous cell carcinoma antigen determinations. Gynecol Oncol. 39:186–194. 1990. View Article : Google Scholar : PubMed/NCBI
72	Yamakawa H, Konno R, Enomoto A, et al: Prognostic factors of uterine cervical cancer. Gan To Kagaku Ryoho. 33:2002–2007. 2006.(In Japanese).
73	te Velde ER, Persijn JP, Ballieux RE and Faber J: Carcinoembryonic antigen serum levels in patients with squamous cell carcinoma of the uterine cervix: clinical significance. Cancer. 49:1866–1873. 1982.
74	Hori T, Ichimura H, Minamihisamatsu M, et al: Chromosomal insertion and amplification of human papillomavirus 16 DNA sequences in a cell line of argyrophil small cell carcinoma of the uterine cervix. Jpn J Cancer Res. 82:371–375. 1991. View Article : Google Scholar : PubMed/NCBI
75	Couturier J, Sastre-Garau X, Schneider-Maunoury S, Labib A and Orth G: Integration of papillomavirus DNA near myc genes in genital carcinomas and its consequences for proto-oncogene expression. J Virol. 65:4534–4538. 1991.PubMed/NCBI
76	Iwasaka T, Yokoyama M, Oh-uchida M, et al: Detection of human papillomavirus genome and analysis of expression of c-myc and Ha-ras oncogenes in invasive cervical carcinomas. Gynecol Oncol. 46:298–303. 1992. View Article : Google Scholar : PubMed/NCBI
77	Pinion SB, Kennedy JH, Miller RW and MacLean AB: Oncogene expression in cervical intraepithelial neoplasia and invasive cancer of cervix. Lancet. 337:819–820. 1991. View Article : Google Scholar : PubMed/NCBI
78	Riou G, Lê MG, Favre M, Jeannel D, Bourhis J and Orth G: Human papillomavirus-negative status and c-myc gene overexpression: independent prognostic indicators of distant metastasis for early-stage invasive cervical cancers. J Natl Cancer Inst. 84:1525–1526. 1992. View Article : Google Scholar
79	Ohta M, Inoue H, Cotticelli MG, et al: The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell. 84:587–597. 1996. View Article : Google Scholar : PubMed/NCBI
80	Machida S, Ohwada M, Saga Y and Suzuki M: Abnormal fragile histidine triad expression in advanced cervical cancer and evaluation of its utility as a prognostic factor. Oncology. 65:89–93. 2003. View Article : Google Scholar : PubMed/NCBI
81	Liao CJ, Wu TI, Huang YH, et al: Glucose-regulated protein 58 modulates cell invasiveness and serves as a prognostic marker for cervical cancer. Cancer Sci. 102:2255–2263. 2011. View Article : Google Scholar : PubMed/NCBI
82	Togami S, Nomoto M, Higashi M, et al: Expression of mucin antigens (MUC1 and MUC16) as a prognostic factor for mucinous adenocarcinoma of the uterine cervix. J Obstet Gynaecol Res. 36:588–597. 2010. View Article : Google Scholar : PubMed/NCBI
83	Hebbar V, Damera G and Sachdev GP: Differential expression of MUC genes in endometrial and cervical tissues and tumors. BMC Cancer. 5:1242005. View Article : Google Scholar : PubMed/NCBI
84	Kodama J, Yoshinouchi M, Seki N, Hongo A, Miyagi Y and Kudo T: Angiogenesis and platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in cervical cancer. Int J Oncol. 15:149–154. 1999.PubMed/NCBI
85	Jussila L and Alitalo K: Vascular growth factors and lymphangiogenesis. Physiol Rev. 82:673–700. 2002.PubMed/NCBI
86	Hashimoto I, Kodama J, Seki N, et al: Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer. Br J Cancer. 85:93–97. 2001. View Article : Google Scholar : PubMed/NCBI
87	Ishikawa F, Miyazono K, Hellman U, et al: Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature. 338:557–562. 1989. View Article : Google Scholar : PubMed/NCBI
88	Fujimoto J, Sakaguchi H, Hirose R, Wen H and Tamaya T: Clinical implication of expression of platelet-derived endothelial cell growth factor (PD-ECGF) in metastatic lesions of uterine cervical cancers. Cancer Res. 59:3041–3044. 1999.PubMed/NCBI
89	Jiang T, Huang L, Wang S and Zhang S: Clinical significance of serum Dkk-3 in patients with gynecological cancer. J Obstet Gynaecol Res. 36:769–773. 2010. View Article : Google Scholar : PubMed/NCBI
90	Hanprasertpong J, Tungsinmunkong K, Chichareon S, et al: Correlation of p53 and Ki-67 (MIB-1) expressions with clinicopathological features and prognosis of early stage cervical squamous cell carcinomas. J Obstet Gynaecol Res. 36:572–580. 2010. View Article : Google Scholar : PubMed/NCBI
91	Shirendeb U, Hishikawa Y, Moriyama S, et al: Human papillomavirus infection and its possible correlation with p63 expression in cervical cancer in Japan, Mongolia, and Myanmar. Acta Histochem Cytochem. 42:181–190. 2009. View Article : Google Scholar : PubMed/NCBI
92	Cimpean AM, Saptefrati L, Ceausu R and Raica M: Characterization of endoglin and Ki-67 expression in endothelial cells from benign and malignant lesions of the uterine cervix. Pathol Int. 59:695–700. 2009. View Article : Google Scholar : PubMed/NCBI
93	Zhang JM, Hashimoto M, Kawai K, et al: CD109 expression in squamous cell carcinoma of the uterine cervix. Pathol Int. 55:165–169. 2005. View Article : Google Scholar : PubMed/NCBI