Sage Journals: Discover world-class research

Abstract

OBJECTIVES:

This study was to explore the prognostic value of connective tissue growth factor (CTGF) expression in endometrial cancer (EC).

METHODS:

We compared CTGF expression in 198 samples from patients with endometrial cancer and 50 samples from patients with healthy endometrial tissues as determined by immunohistochemistry.

RESULTS:

Expression of CTGF was significantly higher in endometrial cancers as compared to normal endometrial tissues. Positive CTGF expression displayed a strong association with CA125 level, histological grade, depth of myometrial invasion and the International Federation of Gynecology and Obstetrics (FIGO) stage. Our findings revealed histological grade, depth of myometrial invasion, FIGO stage, vascular/lymphatic invasion, and the CTGF expression are related to 5-year survival in patients with endometrial cancer. Positive CTGF expression, lymph node status, as well as vascular/lymphatic invasion, were identified as independent prognostic factors in endometrial cancer.

CONCLUTIONS:

Over-expression of CTGF is an independent prognostic factor that will allow the successful differentiation of high-risk population from the group of patients with stage III-IV endometrial cancer. The up-regulation of CTGF may contribute to the progression of endometrial cancer and serve as a new prognostic biomarker in patients with endometrial cancer survival.

Keywords

Endometrial cancer CTGF immunohistochemistry normal endometrial tissues

1. Introduction

Endometrial cancer (EC) is one of the most common malignancies affecting the female reproductive tract [1]. However, the molecular and genetic events underlying the development of these tumors remain obscure [2]. The disease most commonly presents with abnormal uterine bleeding and consequently, is often detected in early stages (FIGO stage I) [3]. However, some patients present with advanced stage disease. 35% of the endometrial cancers are diagnosed in the advanced stage of the disease, and with significantly diminished lifetime expectancy [4]. Hysterectomy with bilateral salpingo-oophorectomy is the primary treatment for patients with this localized disease. Thus, there is an urgent need for new therapeutic targets and strategies for endometrial tumorigenesis, both of which may be realized through improved understanding of the molecular mechanisms governing this disease.

Connective tissue growth factor (CTGF), also known as CCN2, belongs to the CCN (CTGF/Cysteine-rich 61/Nephroblastoma) family [5]. All CCN family members are secreted proteins associated with the extracellular matrix (ECM) which play an essential role in processes such as placentation, embryo implantation, embryogenesis, differentiation, and development. These proteins are also implicated in wound healing, fibrotic disorders, and tumorigenesis [6, 7]. Interestingly, the role of CTGF varies depending on the type of cancer. For example, CTGF is an oncogenic factor which promotes tumor progression in pancreatic, prostate, liver, and breast cancer, ovarian cancer as well as sarcomas [8, 9]. Conversely, CTGF functions as a tumor suppressor in the lung, and oral squamous cell cancers [10, 11, 12]. CTGF has been used as a prognostic marker in esophageal squamous cell carcinoma, gastric and lung cancer [10, 13]. However, the expression pattern and functional mechanisms of CTGF in EC have not been established.

In the present study, we examined the expression of CTGF in normal and malignant endometrial tissue in order to determine its involvement in malignant progression. Additionally, we evaluated whether CTGF expression is associated with clinical-pathologic parameters and prognosis in patients with EC.

2. Materials and methods

2.1 Patient characteristics and specimens

One hundred ninety-eight patients with endometrioid adenocarcinoma were enrolled in the present study. All patients had undergone radical hysterectomy with the same group gynecologists in our institute from January 2007 to December 2008. No neoadjuvant chemotherapy treatment before surgery. All the patients were staged according to the FIGO classification system, and patients with advanced stage received the standard chemotherapy and radiotherapy. The mean age of patients was 53 years (range, 22–75 years). 194 (97.8%) patients without lymph node metastasis and the mean preoperative CA125 levels was 41.72 U/mL (range, 3.14–425.1 U/mL). Besides, 50 endometrial tissues from the cases with hysteromyoma at the same period were included in this study, the mean age was 39 years (range, 34–62 years) and the mean CA125 level was 21.1 U/mL. The Consent forms were got from all cases, and this study was approved by the Ethics Committee of Harbin Medical University Cancer hospital.

Table 1
Connective Tissue Growth Factor (CTGF) Expression in normal endometrial tissues and cancer endometrial tissues

Tissue type	Total No.	High CTGF No. (%)	x2	P
Cancer endometrial	198	103 (52)	20.95	$<$ 0.001
Normal endometrial	50	8 (16)

Abbreviation: CTGF, connective tissue growth factor.

Figure 1.

Representative images of CTGF staining in normal endometrial tissues and endometrial cancers. (a-b) normal endometrial tissues showed negative (a) and 1+ (b) CTGF staining. (c-f) endometrial cancer tissues showed negative (c), 1+ (d), 2+ (e), 3+ (f) CTGF staining, respectively. Magnification 100 $\times$ .

2.2 Immunohistochemistry

For immunohistochemical staining, four $\mu$ m histological sections were deparaffinized with xylene and rehydrated through a graded series of alcohol treatments. Sections were then boiled at 121 ${}^{\circ}$ C for 4 min in 0.01 M citrate buffer (pH 6.0), and endogenous peroxidase was blocked by incubation in 3% H ${}_{2}$ O ${}_{2}$ in methanol for 20 min. Sections were incubated overnight at 4 ${}^{\circ}$ C with a dilution (30 $\mu$ g/ml ) of CTGF primary goat polyclonal antibody (provided by America R&D, AF660). Next, samples were exposed to a biotin-labeled secondary antibody for 30 min. Finally, the slides were counterstained with hematoxylin and eosin (H&E).

2.3 Staining evaluation

The scoring procedure was carried out by two experienced independent pathologists. Evaluation of CTGF expression was scored according to the percentage of positively stained cells in the field of view, as follows: negative (0), no staining; weak (score 1+), 0–19% of cells stained; moderate (score 2+), 20–49% of cell stained; and strong (score 3+), 50–100% of cells stained. Slides with 0 or 1+ staining were classified as low expression, and slides with 2+ or 3+ staining were classified as a high expression [14].

2.4 Statistical analysis

Chi-square tests were applied to analyze the categorical variables. The p-values were shown for the difference of these variables between the CTGF expressions. The 5-year survival rate was analyzed with Kaplan-Meier curve analysis and tested with the log-rank test. COX regression models were performed to test the risk factors. Significance tests were two-tailed and p-values less than 0.05 were considered statistically significant. All analyses were performed using the SPSS statistical (version13.0; SPSS, Chicago, IL, USA) and MedCal.

3. Results

3.1 Expression of CTGF in EC tissues is significantly higher than normal endometrial tissues

CTGF was observed in both glandular and stromal with different coloration. Also, as shown in Fig. 1, CTGF was localized mainly in the cytoplasm or membrane of normal and tumor cells. Normal endometrial tissues exhibited weak or no CTGF immunoreactivity (Fig. 1a and b). However, endometrioid adenocarcinoma tissues showed no or weak CTGF immunoreactivity (Fig. 1c and d), moderate or strong CTGF expression (Fig. 1e and f). As EC specimens were examined, negative CTGF expression was detected in 95 (48%) of 198 patients, whereas positive CTGF expression was detected in 103 (52%) of 198 patients. In normal endometrial tissue, 16% (8 of 50) of samples stained positive for CTGF (Table 1, Fig. 2). As shown in Table 1 and Fig. 2, the level of CTGF was significantly higher in EC tissues compared to the normal endometrial tissue ( $p<$ 0.001).

Figure 2.

Connective tissue growth factor (CTGF) expression in endometrial cancer is significantly higher than normal endometrial tissues ( $P<$ 0.001).

3.2 The relationship between CTGF expression and clinical variables

Relationships between CTGF expression and clinical variables were analyzed for patients with EC. As shown in Table 2, there was no significant correlation between level of CTGF and age ( $p=$ 0.81), blood pressure ( $p=$ 0.76), blood glucose ( $p=$ 0.51), or vascular/lymphatic invasion ( $p=$ 0.15). However, positive CTGF expression showed strong association with CA125 level ( $p=$ 0.02), histological grade ( $p=$ 0.004), depth of myometrial invasion ( $p=$ 0.028), and FIGO stage ( $p=$ 0.025). CTGF was highly expressed and more frequently in poorly differentiated EC than in moderated or well differentiated EC ( $p=$ 0.004). In addition Spearman correlation analysis demonstrated that the CTGF expression is positively correlated with the circulation CA125 levels ( $p<$ 0.0001, $r_{s}=$ 0.618) in EC cancer patients (Fig. 3).

Table 2
Association between CTGF Expression (positive/negative) and Clinicopathologic Parameters

	CTGF low		CTGF high		$x2$	$P$
Age (years)
$\leqslant$ 60	80	(51)	77	(49)
$>$ 60	9	(33.33)	18	(66.67)	2.865	0.091
Hypertension
No	68	(47.55)	75	(52.45)	0.09	0.76
Yes	26	(50)	26	(50)
Diabetes
No	88	(48.89)	92	(51.11)	0.44	0.51
Yes	6	40)	9	(60)
CA125
$\leqslant$ 35	56	(54.37)	47	(45.63)	5.55	0.02
$>$ 35	15	(33.33)	30	(66.67)
Histological grade
G3	6	(20.69)	23	(79.31)		0.004
G2	39	(57.35)	29	(42.65)
G1	50	(49.5)	51	(60.5)
Depth of myometrial invasion
$<$ 1/2	82	(51.9)	76	(48.1)	4.81	0.028
$\geqslant$ 1/2	13	(32.5)	27	(67.5)
FIGO stage
I–II	74	(51.39)	70	(48.61)	5.02	0.025
III–IV	11	(30.56)	25	(69.44)
Vascular/lymphatic invasion #
No	95	(48.97)	99	(51.03)	2.06	0.15
Yes	0	(0)	4	(100)

Abbreviation: FIGO, International Federation of Gynecology and Obstetrics; G1, well differentiated; G2, moderately differentiated; G3, poorly differentiated; # Chi-square corrected.

Figure 3.

Correlation of CTGF staining intensity with CA125. Distribution of CTGF staining intensity in endometrial cancers of different CA125 levels. The $P$ value was determined by spearman rank correlation analysis. CTGF was correlated with CA125 levels. $P<$ 0.0001, $r_{s}=$ 0.618.

3.3 Clinical significance of CTGF expression in EC patients

Table 3 demonstrates CA125 levels ( $p=$ 0.001), lymph node status ( $p<$ 0.001), depth of myometrial invasion ( $p=$ 0.002), FIGO stage ( $p=$ 0.002), vascular/lymphatic invasion ( $p=$ 0.03) and CTGF expression ( $p<$ 0.001) are related to 5-year survival in patients with EC. High CTGF expression was significantly associated with poor survival. As shown in Table 4, the multivariate Cox regression analysis revealed that high CTGF expression ( $p<$ 0.001), lymph node status ( $p<$ 0.001), as well as a vascular/lymphatic invasion ( $p=$ 0.02), are independent prognostic markers for 5-year survival rate in patients with EC. The Kaplan-Meier survival analysis with a log-rank test showed that 5-year survival was significantly lower in patients with high CTGF expression than in patients with low CTGF expression ( $p=$ 0.017, Fig. 4). The 5-year survival rate for patients with positive CTGF expression and patients with negative CTGF expression was 36.8% and 80.9%, respectively ( $p=$ 0.017).

Table 3
Univariate Cox-regression analysis of various clinicopathological parameters and their use as prognostic markers for disease-specific 5-year survival in EC patients

Variables	No. patients	HR/rr	95% CI	$P$
Age (year)
$\leqslant$ 60	157	1
$>$ 60	27	2.08	0.88–4.91	0.095
Hypertension
No	143	1
Yes	52	1.05	0.45–2.47	0.910
Diabetes
No	180	1
Yes	15	0.44	0.06–3.2	0.420
CA125
$\leqslant$ 35	103	1
$>$ 35	45	4.22	1.78–10	0.001
Lymph node status
No	182	1
Yes	16	4.72	2.01–11.06	$<$ 0.001
Histological grade
G1	101	1
G2 vs. G1	68	1.33	0.52–3.43	0.550
G3 vs. G1	29	0.95	0.42–2.14	0.890
Depth of myometrial invasion
$\leqslant$ 1/2	158	1
$>$ 1/2	40	3.2	1.52–6.76	0.002
FIGO stage
1.2	144	1
3.4	36	3.12	1.51–6.43	0.002
Vascular/Lymphatic invasion
No	194	1
Yes	4	5.06	1.18–21.68	0.030
CTGF expression
Low	95	1
High	103	6.28	2.39–16.51	$<$ 0.001

Abbreviation: CI, confidence interval; HR, hazard ratio; G1, well differentiated; G2,moderately differentiated; G3, poorly differentiated; FIGO, International Federation of Gynecology and Obstetrics.

Table 4

Multivariate Cox-regression analysis of various clinicopathological parameters and their use as prognostic markers for disease-specific 5-year survival in EC patients

	SE	$p$	Relative risk	95.0% CI
Lymph node status	0.54	$<$ 0.001	6.21	2.16–17.88
Vascular/lymphatic invasion	0.80	0.020	6.19	1.28–29.90
The CTGF expression	0.64	$<$ 0.001	6.38	1.83–22.29

Figure 4.

Kaplan-Meier survival curves for 198 patients with endometrial cancer, grouped according to CTGF expression. 5-year survival was significantly lower in patients with high CTGF expression than in patients with low CTGF expression ( $p=$ 0.017).

4. Discussion

Historically, the age of onset of EC is mostly after menopause. However, the incidence of EC in premenopausal women has increased dramatically due to earlier-onset obesity in the past ten years [15]. Even though there are effective treatment methods, survival is still based on the stage and histology of the diagnosis. Most EC patients with stage I-II will have a favorable prognosis, whereas patients with stage III or IV will have a worse likelihood of survival [16, 17, 18]. Although CA125 remains as one the most widely used biomarkers for the potential diagnosis and prognosis of EC [19, 20, 21, 22], it demonstrates several limitations, including the occurrence of false-positive diagnosis and over-treatment due to the reduced sensitivity and specificity of CA125 level testing [23, 24]. Therefore, it is of a high clinical significance to find specific valuable biomarkers which can screen high-risk women, make a preoperative stratification of patients as high-risk or low-risk categories, support personalized therapeutic approaches.

In the present study, we detected high CTGF expression in 52% of EC patients, which is significantly higher than 16% in normal endometrial tissues. The CTGF expression was predominantly observed in the cytoplasm and membrane of cancer cells. The rate of positive CTGF expression was increased significantly in poorly-differentiated EC, levels of CA125 expression $ï ¼ ž$ 35 U/mL, depth of myometrial invasion $\geqslant$ 1/2, FIGO stage III-IV. Furthermore, CTGF expression was positively associated with CA125 levels in EC patients. The elevated CA125 level was reported firstly to be an essential predictor for patients with recurrent and advanced EC [25]. Since then, many studies have confirmed that the determination of CA125 before surgery is a prognostic factor for overall survival (OS) and disease-free survival (DFS) in EC [26, 27]. The level of CA125 was significantly higher in patients with more advanced FIGO stage [26]. In the present study, a markedly increased CTGF level was observed in EC patients in FIGO III-IV when compared to FIGO I-II, and the level of CTGF was positively associated with the CA125. Therefore, the CTGF protein level potentially can function as a novel prognostic biomarker to distinguish the EC patients which has more advanced FIGO stage, besides, it has a potential role to predict the poor survival of EC patients.

Interestingly, a recent study demonstrated that CTGF expression was increased in epithelial ovarian cancer tissues, and its expression correlated with the stage of this disease. The CTGF levels in stage III-IV of ovarian cancer were significantly higher than stage I-II [28]. These are consistent with our findings and indicate that over-expression of CTGF may contribute to the progression of EC. The mechanism of CTGF in mediating the EC progression is unclear. However, CTGF had been found to accelerate tumor progression through mediating tumor-stroma interactions between hepatoma cells and hepatic stellate cells [29]. There is a positive feedback loop between CTGF and chemokine ligand 18 in hepatocellular carcinoma metastasis [30]. Thus, promoting tumor-stroma interactions might be one of the mechanisms which are mediated by CTGF to accelerate tumor progression.

Univariate and multivariate analysis revealed that high CTGF expression was a powerful independent predictor for the poor survival of EC patients. The overall 5-year survival rate of EC patients with a positive CTGF expression and a negative CTGF expression was 36.8% and 80.9%, respectively. Our results indicated that over-expression of CTGF might play a role in the aggressive behavior of EC. These are consistent with various studies which showed that CTGF is associated with a more aggressive phenotype and with tumor progression in kind of solid tumor tissues [8, 31, 32, 33, 34, 35, 36, 37, 38, 39]. Dr. Kang and colleagues found that CTGF is a critical component of the gene signature that facilitates osteolytic bone metastasis in breast cancer cells [40]. Administration of FG-3019, a humanized anti-CTGF monoclonal antibody, inhibits tumor growth and metastases in xenograft and orthotopic models of pancreatic cancer in mice [35, 41]. Therefore, CTGF up-regulation in EC may promote the tumor growth and metastases which is associated with a lower survival rate of the patients.

The mechanisms responsible for CTGF over-expression in EC patient needs further investigation to elucidate. Recent studies demonstrated that microRNAs are essential mediators in the mechanism of human cancer. MiR-143 was reported to target CTGF and exert tumor-suppressing functions in epithelial ovarian cancer [42]. In addition to MiR-143, MiR-26b was also found to govern the CTGF expression in osteosarcoma. When MiR-26b levels sharply increased, the CTGF expression was downregulated [43]. Based on these findings, we speculated that MiR-143 and MiR-26b might be a potential regulator of CTGF. However, further investigations are still needed to verify the above-mentioned underlying mechanisms.

In conclusion, our findings indicated that on clinical inspection, EC patients with increased CTGF expression have more chance to develop to the advanced stage of EC and shorter survival time. Mainly, CTGF seemed to be an independent prognostic factor that will allow the successful differentiation of high-risk population from the group of patients with stage III-IV disease. Moreover, CTGF seems to be a novel biomarker for predicting the prognosis of EC patients. Also, over-expression of CTGF in EC patients results in poor survival.

Footnotes

Acknowledgments

I want to express my most profound appreciation to all those who provided me the possibility to complete this manuscript. A special gratitude I give to our department director Dr. Yu, whose contribution to stimulating suggestions and encouragement, helped me to coordinate my clinical work especially in writing this manuscript. Furthermore, I would like to acknowledge with much appreciation for the crucial role of Dr. Jarrett, who provided language help. Special thanks go to my teammate, Dr. Lu, who was involved in conceiving the experimental design.

Conflict of interest

None declared.

References

Bendifallah

Ballester

and Darai

, Endometrial cancer: Predictive models and clinical impact, Bull Cancer 104 (2017), 1022–1031.

Braun

M.M.

Overbeek-Wager

E.A.

and Grumbo

R.J.

, Diagnosis and Management of Endometrial Cancer, Am Fam Physician 93 (2016), 468–74.

Sorosky

J.I.

, Endometrial cancer, Obstet Gynecol 120 (2012), 383–97.

Bohiltea

R.E.

Ancar

Cirstoiu

M.M.

Radoi

Bohiltea

L.C.

and Furtunescu

, Project for the National Program of Early Diagnosis of Endometrial Cancer Part I, J Med Life 8 (2015), 305–14.

Owen

Weeks

H.P.

Zhang

and Jiang

W.G.

, Emerging role of CCN family proteins in tumorigenesis and cancer metastasis (Review), Int J Mol Med 36 (2015), 1451–63.

Ramazani

Knops

Elmonem

M.A.

Nguyen

T.Q.

Arcolino

F.O.

van den Heuvel

Levtchenko

Kuypers

and Goldschmeding

, Connective tissue growth factor (CTGF) from basics to clinics, Matrix Biol 68-69 (2018), 44–66.

Tarr

J.T.

Lambi

A.G.

Bradley

J.P.

Barbe

M.F.

and Popoff

S.N.

, Development of Normal and Cleft Palate: A Central Role for Connective Tissue Growth Factor (CTGF)/CCN2, J Dev Biol 6 (2018).

Chien

O’Kelly

Leiter

Sohn

Yin

Karlan

Vadgama

Lyons

K.M.

and Koeffler

H.P.

, Expression of connective tissue growth factor (CTGF/CCN2) in breast cancer cells is associated with increased migration and angiogenesis, Int J Oncol 38 (2011), 1741–7.

Jia

X.Q.

Cheng

H.Q.

Zhu

Y.H.

Feng

Z.Q.

and Zhang

J.P.

, Inhibition of connective tissue growth factor overexpression decreases growth of hepatocellular carcinoma cells in vitro and in vivo , Chin Med J (Engl) 124 (2011), 3794–9.

10.

Bickelhaupt

Erbel

Timke

Wirkner

Dadrich

Flechsig

Tietz

Pfohler

Gross

Peschke

Hoeltgen

Katus

H.A.

Grone

H.J.

Nicolay

N.H.

Saffrich

Debus

Sternlicht

M.D.

Seeley

T.W.

Lipson

K.E.

and Huber

P.E.

, Effects of CTGF Blockade on Attenuation and Reversal of Radiation-Induced Pulmonary Fibrosis, J Natl Cancer Inst 109 (2017).

11.

Chuang

J.Y.

Yang

W.Y.

Lai

C.H.

Lin

C.D.

Tsai

M.H.

and Tang

C.H.

, CTGF inhibits cell motility and COX-2 expression in oral cancer cells, Int Immunopharmacol 11 (2011), 948–54.

12.

Hatakeyama

S.Y.

Lyons

Y.A.

Pradeep

Wang

Huang

Court

K.A.

Liu

Nie

Rodriguez-Aguayo

Shen

Huang

Hisamatsu

Mitamura

Jennings

Shim

Dorniak

P.L.

Mangala

L.S.

Petrillo

Petyuk

V.A.

Schepmoes

A.A.

Shukla

A.K.

Torres-Lugo

Lee

J.S.

Rodland

K.D.

Fagotti

Lopez-Berestein

and Sood

A.K.

, Role of CTGF in Sensitivity to Hyperthermia in Ovarian and Uterine Cancers, Cell Rep 17 (2016), 1621–1631.

13.

Deng

Y.Z.

Chen

P.P.

Wang

Yin

Koeffler

H.P.

Tong

X.J.

and Xie

, Connective tissue growth factor is overexpressed in esophageal squamous cell carcinoma and promotes tumorigenicity through beta-catenin-T-cell factor/Lef signaling, J Biol Chem 282 (2007), 36571–81.

14.

Chang

C.C.

Shih

J.Y.

Jeng

Y.M.

J.L.

Lin

B.Z.

Chen

S.T.

Chau

Y.P.

Yang

P.C.

and Kuo

M.L.

, Connective tissue growth factor and its role in lung adenocarcinoma invasion and metastasis, J Natl Cancer Inst 96 (2004), 364–75.

15.

Moore

and Brewer

M.A.

, Endometrial Cancer: Is This a New Disease? Am Soc Clin Oncol Educ Book 37 (2017), 435–442.

16.

Lewin

S.N.

Herzog

T.J.

Barrena Medel

N.I.

Deutsch

Burke

W.M.

Sun

and Wright

J.D.

, Comparative performance of the 2009 international Federation of gynecology and obstetrics’ staging system for uterine corpus cancer, Obstet Gynecol 116 (2010), 1141–9.

17.

Lum

M.M.

Belnap

T.W.

Frandsen

Brown

A.P.

Sause

W.T.

Soisson

A.P.

Dodson

M.K.

Werner

and Gaffney

D.K.

, Survival Analysis of Cancer Patients With FIGO Stage IIIA Endometrial Cancer, Am J Clin Oncol 38 (2015), 283–8.

18.

Turkmen

Karalok

Basaran

Kimyon

Kul

Tulunay

Ureyen

and Turan

, Revaluating the survival effects of International Federation of Gynecology and Obstetrics 1988 stage IIIA criteria for endometrial cancer, J Turk Ger Gynecol Assoc 18 (2017), 110–115.

19.

Nicklin

Janda

Gebski

Jobling

Land

Manolitsas

McCartney

Nascimento

Perrin

Baker

J.F.

Obermair

and Investigators

L.T.

, The utility of serum CA-125 in predicting extra-uterine disease in apparent early-stage endometrial cancer, Int J Cancer 131 (2012), 885–90.

20.

Patsner

and Yim

G.W.

, Predictive value of preoperative serum CA-125 levels in patients with uterine cancer: The Asian experience 2000 to 2012, Obstet Gynecol Sci 56 (2013), 281–8.

21.

Atguden

Yildiz

Aksut

Yalcin

S.E.

Yalcin

Uysal

and Yetimalar

, The Value of Preoperative CA 125 Levels in Prediction of Myometrial Invasion in Patients with Early-stage Endometrioid- type Endometrial Cancer, Asian Pac J Cancer Prev 17 (2016), 497–501.

22.

Chen

Y.L.

Huang

C.Y.

Chien

T.Y.

Huang

S.H.

C.J.

and Ho

C.M.

, Value of pre-operative serum CA125 level for prediction of prognosis in patients with endometrial cancer, Aust N Z J Obstet Gynaecol 51 (2011), 397–402.

23.

Rizner

T.L.

, Discovery of biomarkers for endometrial cancer: current status and prospects, Expert Rev Mol Diagn 16 (2016), 1315–1336.

24.

Motoo

Watanabe

and Sawabu

, Sensitivity and specificity of tumor markers in cancer diagnosis, Nihon Rinsho 54 (1996), 1587–91.

25.

Niloff

J.M.

Klug

T.L.

Schaetzl

Zurawski

V.R.

, Jr. Knapp

R.C.

and Bast

R.C.

, Jr., Elevation of serum CA125 in carcinomas of the fallopian tube, endometrium, and endocervix, Am J Obstet Gynecol 148 (1984), 1057–8.

26.

Kotowicz

Fuksiewicz

Jonska-Gmyrek

Wagrodzki

and Kowalska

, Preoperative serum levels of YKL 40 and CA125 as a prognostic indicators in patients with endometrial cancer, Eur J Obstet Gynecol Reprod Biol 215 (2017), 141–147.

27.

Jiang

Huang

and Zhang

, Preoperative serum CA125: a useful marker for surgical management of endometrial cancer, BMC Cancer 15 (2015), 396.

28.

Gery

Xie

Yin

Gabra

Miller

Wang

Scott

W.S.

Popoviciu

M.L.

Said

J.W.

and Koeffler

H.P.

, Ovarian carcinomas: CCN genes are aberrantly expressed and CCN1 promotes proliferation of these cells, Clin Cancer Res 11 (2005), 7243–54.

29.

Makino

Hikita

Kodama

Shigekawa

Yamada

Sakamori

Eguchi

Morii

Yokoi

Mukoyama

Hiroshi

Tatsumi

and Takehara

, CTGF Mediates Tumor-Stroma Interactions between Hepatoma Cells and Hepatic Stellate Cells to Accelerate HCC Progression, Cancer Res 78 (2018), 4902–4914.

30.

Wang

T.T.

Yuan

J.H.

J.Z.

Yang

W.J.

Liu

X.N.

Yin

Y.P.

Liu

Pan

and Sun

S.H.

, CTGF secreted by mesenchymal-like hepatocellular carcinoma cells plays a role in the polarization of macrophages in hepatocellular carcinoma progression, Biomed Pharmacother 95 (2017), 111–119.

31.

Wang

M.Y.

Chen

P.S.

Prakash

Hsu

H.C.

Huang

H.Y.

Lin

M.T.

Chang

K.J.

and Kuo

M.L.

, Connective tissue growth factor confers drug resistance in breast cancer through concomitant up-regulation of Bcl-xL and cIAP1, Cancer Res 69 (2009), 3482–91.

32.

Mao

Rong

Cui

Wang

Zhang

and Jin

, Connective tissue growth factor enhances the migration of gastric cancer through downregulation of E-cadherin via the NF-kappaB pathway, Cancer Sci 102 (2011), 104–10.

33.

Liu

L.Y.

Han

Y.C.

S.H.

and Lv

Z.H.

, Expression of connective tissue growth factor in tumor tissues is an independent predictor of poor prognosis in patients with gastric cancer, World J Gastroenterol 14 (2008), 2110–4.

34.

Xie

Yin

Wang

H.J.

Liu

G.T.

Elashoff

Black

and Koeffler

H.P.

, Levels of expression of CYR61 and CTGF are prognostic for tumor progression and survival of individuals with gliomas, Clin Cancer Res 10 (2004), 2072–81.

35.

Dornhofer

Spong

Bennewith

Salim

Klaus

Kambham

Wong

Kaper

Sutphin

Nacamuli

Hockel

Longaker

Yang

Koong

and Giaccia

, Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis, Cancer Res 66 (2006), 5816–27.

36.

Xiang

Z.L.

Zeng

Z.C.

Tang

Z.Y.

Fan

Zeng

H.Y.

and Zhu

X.D.

, Potential prognostic biomarkers for bone metastasis from hepatocellular carcinoma, Oncologist 16 (2011), 1028–39.

37.

Zhou

Z.Q.

Cao

W.H.

Xie

J.J.

Lin

Shen

Z.Y.

Zhang

Q.Y.

Shen

J.H.

L.Y.

and Li

E.M.

, Expression and prognostic significance of THBS1, Cyr61 and CTGF in esophageal squamous cell carcinoma, BMC Cancer 9 (2009), 291.

38.

Wang

Zhang

Meng

Liu

Wang

Lin

and Chen

, Expression and clinical significance of connective tissue growth factor in thyroid carcinomas, J Int Med Res 41 (2013), 1214–20.

39.

Gorlov

I.P.

Sircar

Zhao

Maity

S.N.

Navone

N.M.

Gorlova

O.Y.

Troncoso

Pettaway

C.A.

Byun

J.Y.

and Logothetis

C.J.

, Prioritizing genes associated with prostate cancer development, BMC Cancer 10 (2010), 599.

40.

Kang

Siegel

P.M.

Shu

Drobnjak

Kakonen

S.M.

Cordon-Cardo

Guise

T.A.

and Massague

, A multigenic program mediating breast cancer metastasis to bone, Cancer Cell 3 (2003), 537–49.

41.

Aikawa

Gunn

Spong

S.M.

Klaus

S.J.

and Korc

, Connective tissue growth factor-specific antibody attenuates tumor growth, metastasis, and angiogenesis in an orthotopic mouse model of pancreatic cancer, Mol Cancer Ther 5 (2006), 1108–16.

42.

Wang

and Li

, MiR-143 targets CTGF and exerts tumor-suppressing functions in epithelial ovarian cancer, Am J Transl Res 8 (2016), 2716–26.

43.

Duan

Ren

Zhang

and Feng

, MicroRNA-26b inhibits metastasis of osteosarcoma via targeting CTGF and Smad1, Tumour Biol 36 (2015), 6201–9.

Overexpression of connective tissue growth factor is associated with tumor progression and unfavorable prognosis in endometrial cancer

Abstract

OBJECTIVES:

METHODS:

RESULTS:

CONCLUTIONS:

Keywords

1. Introduction

2. Materials and methods

2.1 Patient characteristics and specimens

Table 1 Connective Tissue Growth Factor (CTGF) Expression in normal endometrial tissues and cancer endometrial tissues

2.3 Staining evaluation

2.4 Statistical analysis

3. Results

3.1 Expression of CTGF in EC tissues is significantly higher than normal endometrial tissues

Table 2 Association between CTGF Expression (positive/negative) and Clinicopathologic Parameters

Table 3 Univariate Cox-regression analysis of various clinicopathological parameters and their use as prognostic markers for disease-specific 5-year survival in EC patients

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Connective Tissue Growth Factor (CTGF) Expression in normal endometrial tissues and cancer endometrial tissues

Table 2
Association between CTGF Expression (positive/negative) and Clinicopathologic Parameters

Table 3
Univariate Cox-regression analysis of various clinicopathological parameters and their use as prognostic markers for disease-specific 5-year survival in EC patients