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Archives of Gynecology and Obstetrics

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01-08-2016 | Gynecologic Oncology

CPE overexpression is correlated with pelvic lymph node metastasis and poor prognosis in patients with early-stage cervical cancer

Authors: Hong-wei Shen, Jin-feng Tan, Jian-hong Shang, Min-zhi Hou, Jun Liu, Li He, Shu-zhong Yao, Shan-yang He

Published in: Archives of Gynecology and Obstetrics | Issue 2/2016

Abstract

Purpose

Elevated carboxypeptidase E (CPE) levels play crucial roles in tumorigenesis and metastasis. This study investigated the expression and clinicopathological significance of CPE in early-stage cervical cancer.

Methods

Elevated carboxypeptidase E expression was analyzed using quantitative polymerase chain reaction and western blotting in normal cervical tissue, cervical cancer cell lines, and in cervical cancer tissues and adjacent noncancerous tissues (ANTs) from the same patient. Immunohistochemistry (IHC) was used to examine CPE expression in tissue samples from 112 patients with early-stage cervical cancer (FIGO stages Ia2–IIa2), 60 patients with cervical intraepithelial neoplasia, and 19 patients with normal cervical tissues (NCTs). Associations between CPE expression and prognostic and diagnostic factors were evaluated statistically.

Results

CPE expression was significantly higher in cervical cancer cell lines and tissues than in normal tissues and ANTs. Semi-quantitative analysis of IHC indicated that CPE gradually increased from CIN I to cervical cancer, but was absent in NCTs. CPE expression was seen in 40.2 % (45/112) of the cervical cancer samples. CPE expression was significantly associated with FIGO stage (P = 0.003), tumor size (P = 0.012), stromal invasion (P < 0.001), lymphovascular space invasion (P = 0.016), parametrial infiltration (P = 0.027), vaginal involvement (P = 0.007), postoperative adjuvant therapy (P = 0.024), recurrence (P < 0.001), survival (P < 0.001), and pelvic lymph node metastasis (PLNM) (P < 0.001), and it was significantly higher in tissues from patients with PLNM than without PLNM. Logistic regression analysis identified high-level CPE expression as an independent risk factor for PLNM (P = 0.001). Patients with higher CPE expression had shorter overall survival duration than patients with lower CPE expression. Univariate and multivariate Cox-regression analyses suggested that high-level CPE expression is an independent prognostic factor for overall survival in early-stage cervical cancer.

Conclusions

High-level CPE expression was associated with a poor prognosis in early-stage cervical cancer. CPE may serve as a biomarker for predicting PLNM and survival in these patients.

Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90CrossRefPubMed

Gien LT, Covens A (2009) Lymph node assessment in cervical cancer: prognostic and therapeutic implications. J Surg Oncol 99:242–247CrossRefPubMed

Noguchi H, Shiozawa I, Sakai Y, Yamazaki T, Fukuta T (1987) Pelvic lymph node metastasis of uterine cervical cancer. Gynecol Oncol 27:150–158CrossRefPubMed

Morice P, Castaigne D, Pautier P, Rey A, Haie-Meder C, Leblanc M, Duvillard P (1999) Interest of pelvic and paraaortic lymphadenectomy in patients with stage IB and II cervical carcinoma. Gynecol Oncol 73:106–110CrossRefPubMed

Lai CH, Hong JH, Hsueh S, Ng KK, Chang TC, Tseng CJ, Chou HH, Huang KG (1999) Preoperative prognostic variables and the impact of postoperative adjuvant therapy on the outcomes of Stage IB or II cervical carcinoma patients with or without pelvic lymph node metastases: an analysis of 891 cases. Cancer 85:1537–1546CrossRefPubMed

Cao DY, Yang JX, Wu XH et al (2013) Comparisons of vaginal and abdominal radical trachelectomy for early-stage cervical cancer: preliminary results of a multi-center research in China. Br J Cancer 109:2778–2782CrossRefPubMedPubMedCentral

Rob L, Pluta M, Strnad P, Hrehorcak M, Chmel R, Skapa P, Robova H (2008) A less radical treatment option to the fertility-sparing radical trachelectomy in patients with stage I cervical cancer. Gynecol Oncol 111:S116–S120CrossRefPubMed

Landoni F, Maneo A, Colombo A et al (1997) Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 350:535–540CrossRefPubMed

Selman TJ, Mann C, Zamora J, Appleyard TL, Khan K (2008) Diagnostic accuracy of tests for lymph node status in primary cervical cancer: a systematic review and meta-analysis. CMAJ 178:855–862CrossRefPubMedPubMedCentral

10.

Mitchell DG, Snyder B, Coakley F et al (2009) Early invasive cervical cancer: MRI and CT predictors of lymphatic metastases in the ACRIN 6651/183 intergroup study. Gynecol Oncol 112:95–103CrossRefPubMed

11.

Lv K, Guo HM, Lu YJ, Wu ZX, Zhang K, Han JK (2014) Role of 18F-FDG PET/CT in detecting pelvic lymph-node metastases in patients with early-stage uterine cervical cancer: comparison with MRI findings. Nucl Med Commun 35:1204–1211CrossRefPubMed

12.

Altgassen C, Hertel H, Brandstädt A, Köhler C, Dürst M, Schneider A, AGO Study Group (2008) Multicenter validation study of the sentinel lymph node concept in cervical cancer: AGO Study Group. J Clin Oncol 26:2943–2951CrossRefPubMed

13.

Wang W, Jia HL, Huang JM, Liang YC, Tan H, Geng HZ, Guo LY, Yao SZ (2014) Identification of biomarkers for lymph node metastasis in early-stage cervical cancer by tissue-based proteomics. Br J Cancer 110:1748–1758CrossRefPubMedPubMedCentral

14.

Liu L, Xia M, Wang J, Zhang W, Zhang Y, He M (2014) CISD2 expression is a novel marker correlating with pelvic lymph node metastasis and prognosis in patients with early-stage cervical cancer. Med Oncol 31:183CrossRefPubMed

15.

Zhang X, Zheng Z, Yingji S, Kim H, Jin R, Renshu L, Lee DY, Roh MR, Yang S (2014) Downregulation of glutathione peroxidase 3 is associated with lymph node metastasis and prognosis in cervical cancer. Oncol Rep 31:2587–2592PubMed

16.

Liu Z, Shi Y, Meng W, Liu Y, Yang K, Wu S, Peng Z (2014) Expression and localization of maspin in cervical cancer and its role in tumor progression and lymphangiogenesis. Arch Gynecol Obstet 289:373–382CrossRefPubMed

17.

Huang L, Liao LM, Liu AW, Wu JB, Cheng XL, Lin JX, Zheng M (2014) Overexpression of long noncoding RNA HOTAIR predicts a poor prognosis in patients with cervical cancer. Arch Gynecol Obstet 290:717–723CrossRefPubMed

18.

Cawley NX, Wetsel WC, Murthy SR, Park JJ, Pacak K, Loh YP (2012) New roles of carboxypeptidase E in endocrine and neural function and cancer. Endocr Rev 33:216–253CrossRefPubMedPubMedCentral

19.

Billova S, Galanopoulou AS, Seidah NG, Qiu X, Kumar U (2007) Immunohistochemical expression and colocalization of somatostatin, carboxypeptidase-E and prohormone convertases 1 and 2 in rat brain. Neuroscience 147:403–418CrossRefPubMed

20.

Cawley NX, Zhou J, Hill JM et al (2004) The carboxypeptidase E knockout mouse exhibits endocrinological and behavioral deficits. Endocrinology 145:5807–5819CrossRefPubMed

21.

Cawley NX, Yanik T, Woronowicz A, Chang W, Marini JC, Loh YP (2010) Obese carboxypeptidase E knockout mice exhibit multiple defects in peptide hormone processing contributing to low bone mineral density. Am J Physiol Endocrinol Metab 299:E189–E197PubMedPubMedCentral

22.

Woronowicz A, Koshimizu H, Chang SY et al (2008) Absence of carboxypeptidase E leads to adult hippocampal neuronal degeneration and memory deficits. Hippocampus 18:1051–1063CrossRefPubMedPubMedCentral

23.

Murthy SR, Pacak K, Loh YP (2010) Carboxypeptidase E: elevated expression correlated with tumor growth and metastasis in pheochromocytomas and other cancers. Cell Mol Neurobiol 30:1377–1381CrossRefPubMedPubMedCentral

24.

Tang SS, Zhang JH, Liu HX, Li HZ (2009) PC2/CPE-mediated pro-protein processing in tumor cells and its differentiated cells or tissues. Mol Cell Endocrinol 303:43–49CrossRefPubMed

25.

Hong Y, Ho KS, Eu KW, Cheah PY (2007) A susceptibility gene set for early onset colorectal cancer that integrates diverse signaling pathways: implication for tumorigenesis. Clin Cancer Res 13:1107–1114CrossRefPubMed

26.

Krajnik M, Schäfer M, Sobanski P, Kowalewski J, Bloch-Boguslawska E, Zylicz Z, Mousa SA (2010) Enkephalin, its precursor, processing enzymes, and receptor as part of a local opioid network throughout the respiratory system of lung cancer patients. Hum Pathol 41:632–642CrossRefPubMed

27.

Bachtiary B, Boutros PC, Pintilie M et al (2006) Gene expression profiling in cervical cancer: an exploration of intratumor heterogeneity. Clin Cancer Res 12:5632–5640CrossRefPubMed

28.

Benedet JL, Bender H, Jones H 3rd, Ngan HY, Pecorelli S (2000) FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 70:209–262CrossRefPubMed

29.

Delgado G, Bundy B, Zaino R, Sevin BU, Creasman WT, Major F (1990) Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinomaof the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 38:352–357CrossRefPubMed

30.

Sun JR, Zhang YN, Sun XM, Feng SY, Yan M (2011) Prediction model of pelvic lymph node metastasis in early stage cervical cancer and its clinical value. Minerva Chir 66:537–545PubMed

31.

Lee TK, Murthy SR, Cawley NX et al (2011) An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers. J Clin Invest 121:880–892CrossRefPubMedPubMedCentral

32.

Murthy SR, Dupart E, Al-Sweel N, Chen A, Cawley NX, Loh YP (2013) Carboxypeptidase E promotes cancer cell survival, but inhibits migration and invasion. Cancer Lett 341:204–213CrossRefPubMed

33.

Skalka N, Caspi M, Caspi E, Loh YP, Rosin-Arbesfeld R (2012) Carboxypeptidase E: a negative regulator of the canonical Wnt signaling pathway. Oncogene 32:2836–2847CrossRefPubMedPubMedCentral

34.

Liu A, Shao C, Jin G, Liu R, Hao J, Shao Z, Liu Q, Hu X (2014) Downregulation of CPE regulates cell proliferation and chemosensitivity in pancreatic cancer. Tumour Biol 35:12459–12465CrossRefPubMed

35.

Sima N, Cheng X, Ye F, Ma D, Xie X, Lü W (2013) The overexpression of scaffolding protein NEDD9 promotes migration and invasion in cervical cancer via tyrosine phosphorylated FAK and SRC. PLoS One 8:e74594CrossRefPubMedPubMedCentral

Title: CPE overexpression is correlated with pelvic lymph node metastasis and poor prognosis in patients with early-stage cervical cancer
Authors: Hong-wei Shen
Jin-feng Tan
Jian-hong Shang
Min-zhi Hou
Jun Liu
Li He
Shu-zhong Yao
Shan-yang He
Publication date: 01-08-2016
Publisher: Springer Berlin Heidelberg
Published in: Archives of Gynecology and Obstetrics / Issue 2/2016
Print ISSN: 0932-0067
Electronic ISSN: 1432-0711
DOI: https://doi.org/10.1007/s00404-015-3985-6

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

CPE overexpression is correlated with pelvic lymph node metastasis and poor prognosis in patients with early-stage cervical cancer

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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