Skip to main content
Erschienen in: Archives of Gynecology and Obstetrics 2/2016

22.12.2015 | Gynecologic Oncology

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

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

Erschienen in: Archives of Gynecology and Obstetrics | Ausgabe 2/2016

Einloggen, um Zugang zu erhalten

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.
Literatur
1.
Zurück zum Zitat Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90CrossRefPubMed Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90CrossRefPubMed
2.
Zurück zum Zitat Gien LT, Covens A (2009) Lymph node assessment in cervical cancer: prognostic and therapeutic implications. J Surg Oncol 99:242–247CrossRefPubMed Gien LT, Covens A (2009) Lymph node assessment in cervical cancer: prognostic and therapeutic implications. J Surg Oncol 99:242–247CrossRefPubMed
3.
Zurück zum Zitat Noguchi H, Shiozawa I, Sakai Y, Yamazaki T, Fukuta T (1987) Pelvic lymph node metastasis of uterine cervical cancer. Gynecol Oncol 27:150–158CrossRefPubMed Noguchi H, Shiozawa I, Sakai Y, Yamazaki T, Fukuta T (1987) Pelvic lymph node metastasis of uterine cervical cancer. Gynecol Oncol 27:150–158CrossRefPubMed
4.
Zurück zum Zitat 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 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
5.
Zurück zum Zitat 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 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
6.
Zurück zum Zitat 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 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
7.
Zurück zum Zitat 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 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
8.
Zurück zum Zitat 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 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
9.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat Cawley NX, Zhou J, Hill JM et al (2004) The carboxypeptidase E knockout mouse exhibits endocrinological and behavioral deficits. Endocrinology 145:5807–5819CrossRefPubMed Cawley NX, Zhou J, Hill JM et al (2004) The carboxypeptidase E knockout mouse exhibits endocrinological and behavioral deficits. Endocrinology 145:5807–5819CrossRefPubMed
21.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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
Metadaten
Titel
CPE overexpression is correlated with pelvic lymph node metastasis and poor prognosis in patients with early-stage cervical cancer
verfasst von
Hong-wei Shen
Jin-feng Tan
Jian-hong Shang
Min-zhi Hou
Jun Liu
Li He
Shu-zhong Yao
Shan-yang He
Publikationsdatum
22.12.2015
Verlag
Springer Berlin Heidelberg
Erschienen in
Archives of Gynecology and Obstetrics / Ausgabe 2/2016
Print ISSN: 0932-0067
Elektronische ISSN: 1432-0711
DOI
https://doi.org/10.1007/s00404-015-3985-6

Weitere Artikel der Ausgabe 2/2016

Archives of Gynecology and Obstetrics 2/2016 Zur Ausgabe

Update Gynäkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert – ganz bequem per eMail.