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Abstract

OBJECTIVES:

To investigate TCF4 expression in epithelial ovarian cancer, and to explore its correlation with clinicopathological parameters and clinical prognosis of epithelial ovarian cancer.

METHODS:

From 2009 to 2017, 188 cases of paraffin-embedded epithelial ovarian cancer tissues and 41 paratumor ovarian tissues which had been confirmed at the memorial hospital of Sun Yat-sen University were collected in this study, and the expression of TCF4 was performed by immunohistochemistry using a polyclonal antibody specific for TCF4.

RESULTS:

The expression of TCF4 protein was associated with disease progression free survival and overall survival in epithelial ovarian cancer patients; and TCF4 overexpression was associated with age, FIGO stage, lymph node metastasis, intraperitoneal metastasis, intestinal metastasis, vital status, intraperitoneal recurrence, and serum CA153. Moreover, in a multivariate Cox regression analysis TCF4 overexpression was an indeed independent prognostic factor in epithelial ovarian cancer.

CONCLUSIONS:

TCF4 may play an oncogenic role in epithelial ovarian cancer, and TCF4 is a useful independent prognostic biomarker of epithelial ovarian cancer, and it may provide a candidate target therapy treatment in future.

Keywords

TCF4 ovarian cancer expression clinical significance

1. Introduction

Ovarian cancer is the first leading cause of cancer death in female genital malignant tumors. Approximately 238,700 women are annually diagnosed with this disease worldwide, and about 151,900 associated deaths [1]. The prognosis of epithelial ovarian cancer patients remains poor, which is because of the lack of specific symptoms and the absence of effective early diagnostic method [2, 3], so emphasizing the development of new diagnostic and treatment strategies is very ugent. Recently serum biomarkers such as serum CA125 and HE4 have been used to monitor the diagnose, treatment effect, progress and prognosis of epithelial ovarian cancer, and also have been used to detect the recurrence of disease after cytoreductive surgery or chemotherapy. However, these biomarkers are neither extremely sensitive nor particularly specific. So it is important to develop novel diagnostic and treatment strategies.

The Wnt/ $\beta$ -catenin signal pathway involves in regulating many important cellular processes, including cancer development and differentiation, cell apoptosis, immunologic and inflammatory responses, cell-cycle progression and cellular division [4, 5]. Transcription factor 4 (TCF4) is a key molecule of the Wnt signaling pathway, which can interact with $\beta$ -catenin and act as a transcriptional factor in the nucleus [4, 6]. In certain cell types, TCF4 is emerging as an important regulator of epithelial-mesenchymal transition (EMT) [7] which plays an important role during embryonic development, in tissue repair, and in cancer metastasis. several lines of convergent evidence support a role for TCF4 as an EMT regulator in different cells [8]. However, to the best of our knowledge, there has been no reports which described the clinicopathological parameter and clinical significance of TCF4 expression in the development and progression of epithelial ovarian cancer.

In this study, we aimed to investigate the expression, clinicopathological parameters, and clinical significance of TCF4 in 188 cases patients with paraffin-embedded epithelial ovaria cancer tissues.

2. Materials and methods

2.1 Paraffin-embedded ovarian cancer tissue samples

From 2009 to 2017, a total of 188 cases of paraffin-embedded epithelial ovarian cancer tissues and 41 paratumor ovarian tissues which had been confirmed pathologically at the memorial hospital of Sun Yat-sen University were collected in this study. Survival time was calculated from the operation date until 14 April 2018 when any remaining survivors were censored. This trial was obtained ethics approval from the memorial hospital of Sun Yat-sen University Ethics Committee.

Figure 1.

Comparison and representative photomicrographs of ovarian cancer/paratumor tissues immunohistochemically stained for TCF4: A. Comparison of ovarian cancer and paratumor tissues immunohistochemically stained for TCF4; B. Representative photomicrographs of ovarian cancer and paratumor tissues immunohistochemically stained for TCF4 (400 $\times$ ); C. Representative photomicrographs of TCF4 expression in epithelial ovarian cancer(400 $\times$ and 200 $\times$ ).

2.2 Immunohistochemistry

The TCF4 protein expression in epithelial ovarian cancer tissues and paratumor tissues were all detected by immunohistochemical technology. The step was following, 4 $\mu$ m-thick paraffin-embedded sections were baked at 65 ${}^{\circ}$ C for 2 h, deparaffinized with xylene, rehydrated, and microwaved in antigen retrieval buffer. Then, high tension was used for antigen retrieval, and the specimens were treated with 3% hydrogen peroxide in methanol to quench the endogenous peroxidase activity, and then incubated with 1% bovine serum albumin to block nonspecific binding, and incubated with anti-rabbit TCF4 polyclonal antibodies (1:100; protech) at 4 ${}^{\circ}$ C overnight. Next day, the sections were treated with anti-rabbit secondary antibody (Sigma) after DDH ${}_{2}$ O and PBS washing, and then incubated with streptavidin horseradish peroxidase complex (Sigma), immersed in 3-amino-9-ethyl carbazole. At last, the sections were then counterstained with 10% Mayer’s hematoxylin, dehydrated, and mounted in Crystal Mount. Two pathologists evaluated the degree of immunostaining of each formalin-fixed section. The score was due to both the proportion of positively stained cancer cells and the intensity of staining. The percentage of cancer cells was scored as follows: sections with $<$ 10% positive cancer cells were scored as 0; 10–50% positive cancer cells were scored as 1; 50–75% positive cancer cells were scored as 2; and $>$ 75% positive cancer cells were scored as 3. Meanwhile, the tissues were sorted into four grades based on staining intensity, as follows: 0 indicated no staining; 1 indicated weak staining (light yellow); 2 moderate staining (yellow brown); and 3 strong staining (brown). The staining index (0–9) was calculated as the product of the proportion of positive cells multiplied by the staining intensity score. The best cutoff value was defined as follows: a staining score of $\geqslant$ 6 was considered to have high TCF4 expression, and a staining score of $\leqslant$ 4 indicated low TCF4 expression [9]. The TCF4 protein expression in epithelial ovarian cancer tissues and paratumor tissues were all detected by immunohistochemical technology. The step was following, 4 $\mu$ m-thick paraffin-embedded sections were baked at 65 ${}^{\circ}$ C for 2 h, deparaffinized with xylene, rehydrated, and microwaved in antigen retrieval buffer. Then, high tension was used for antigen retrieval, and the specimens were treated with 3% hydrogen peroxide in methanol to quench the endogenous peroxidase activity, and then incubated with 1% bovine serum albumin to block nonspecific binding, and incubated with anti-rabbit TCF4 polyclonal antibodies (1:100; protech) at 4 ${}^{\circ}$ C overnight. Next day, the sections were treated with anti-rabbit secondary antibody (Sigma) after DDH2O and PBS washing, and then incubated with streptavidin horseradish peroxidase complex (Sigma), immersed in 3-amino-9-ethyl carbazole. At last, the sections were then counterstained with 10% Mayer’s hematoxylin, dehydrated, and mounted in Crystal Mount. Two pathologists evaluated the degree of immunostaining of each formalin-fixed section. The score was due to both the proportion of positively stained cancer cells and the intensity of staining. The percentage of cancer cells was scored as follows: sections with $<$ 10% positive cancer cells were scored as 0; 10–50% positive cancer cells were scored as 1; 50–75% positive cancer cells were scored as 2; and $>$ 75% positive cancer cells were scored as 3. Meanwhile, the tissues were sorted into four grades based on staining intensity, as follows: 0 indicated no staining; 1 indicated weak staining (light yellow); 2 moderate staining (yellow brown); and 3 strong staining (brown). The staining index (0–9) was calculated as the product of the proportion of positive cells multiplied by the staining intensity score. The best cutoff value was defined as follows: a staining score of $\geqslant$ 6 was considered to have high TCF4 expression, and a staining score of $\leqslant$ 4 indicated low TCF4 expression [9].

Figure 2.

TCF4 protein overexpression is associated with disease progression free and overall survival in epithelial ovarian cancer patients.

2.3 Statistical analysis

All of the statistical analyses were calculated with the statistical software package SPSS 21.0. The $\chi^{2}$ test and Fisher’s exact test were used to analyze the relationship between TCF4 protein expression and clinicopathological parameters. In addition, patients’ survival were determined by a Kaplan-Meier analysis, and the differences were counted by the log-rank test. Cox’s proportional hazards regression model was used to the univariate and multivariate analysis. A $p$ value of $<$ 0.05 in all of the analyses was considered statistically significant.

3. Results

3.1 Comparison and representative photomicrographs of ovarian cancer/paratumor tissues immunohistochemically stained for TCF4

In 188 cases of ovarian cancer tissues stained with the TCF4 specific antibody, 21/188 (11.17%) had weak/absent staining (also called low expression) and 167/188 (88.83%) had strong/moderate staining (also called high expression), while in 41 ovarian paratumor tissues, 19/41 (46.34%) had weak/absent staining and 22/41 (53.66%) had strong/moderate staining, and there was significant difference between the two groups ( $P<$ 0.0001) (Fig. 1A). In addition, in 188 cases of ovarian cancer tissues stained with the TCF4 specific antibody, 5 cases had absent staining, 16 cases had weak staining, 59 cases had moderate staining, and 108 cases had strong staining (Fig. 1C). Moreover, we found that TCF4 expression staining located at cytoplasmic (Fig. 1B).

3.2 TCF4 protein overexpression was associated with disease progression free and overall survival in epithelial ovarian cancer patients

In order to determine whether TCF4 expression was associated with epithelial ovarian cancer patients survival, we stained 188 epithelial ovarian cancer cases and 41 paired ovarian paratumor tissues using immunohistochemistry with a rabbit polyclonal antibody specific for TCF4. Kaplan-Meier survival analysis demonstrated that there was a statistically significance on disease progression free survival between high and low expression of TCF4 ( $P=$ 0.049). Moreover, there was also a statistically significant difference on overall survival ( $P=$ 0.019) (Fig. 2). The Kaplan-Meier survival analysis showed that the cumulative overall survival (OS) and disease progression free survival (PFS) rates of epithelial ovarian cancer patients decreased with increase of TCF4 protein expression. Patients with TCF4 high expression showed a median survival time of only 24 months and a median PFS time of only 10 months, but these values in patients with TCF4 low expression were 34 and 19 months, respectively.

3.3 TCF4 overexpression was correlated with the clinical features of ovarian cancer

Subsequently, we studied that TCF4 overexpression was correlated with the clinical parameters of epithelial ovarian cancer. The percentages of patients with stages I, II, III, and IV tumors were 14.36%, 11.17%, 58.51%, and 15.96%, respectively (Table 1).

Table 1
Clinicopathological parameters and tumor expression of TCF4 in epithelial ovarian cancer

Characteristic	Number of cases (%)
Age (years)
$\leqslant$ 50	94 (50.00)
$>$ 50	94 (50.00)
FIGO stage
I	27 (14.36)
II	21 (11.17)
III	110 (58.51)
IV	30 (15.96)
Histological type
Serous adenocarcinoma	112 (70.44)
Mucoid adenocarcinoma	11 (6.92)
Endometrial adenocarcinoma	25 (15.72)
Clear cell carcinoma	11 (6.92)
Lymph node metastasis
Absent	51 (61.45)
Present	32 (38.55)
Intraperitoneal metastasis
No	60 (31.91)
Yes	128 (68.09)
Intestinal metastasis
No	97 (51.60)
Yes	91 (48.40)
Expression of TCF4
None or low	21 (11.17)
Moderate or high	167 (88.83)
Vital status (at last follow-up)
Alive	35 (38.46)
Dead	56 (61.54)
Intraperitoneal recurrence
No	135 (73.37)
Yes	49 (26.63)
Distant recurrence
No	161 (87.50)
Yes	23 (12.50)
Residual tumor size (cm)
$\leqslant$ 1	171 (90.96)
$>$ 1	17 (9.04)
Differentiation grade
G1/G2	78 (44.57)
G3	97 (55.43)
Neoadjuvant chemotherapy
No	168 (89.36)
Yes	20 (10.64)
Postoperative chemotherapy
No	9 (4.79)
Yes	179 (95.21)
Hyperthermic intraperitoneal chemotherapy
No	162 (86.17)
Yes	26 (13.83)
Ascites see tumor cells ( $+$ )
No	43 (51.19)
Yes	41 (48.81)
Cytoreductive surgery
No	3 (1.60)
Yes	185 (98.40)
Platinum resistance
No	184 (97.87)
Yes	4 (2.13)

In addtion, the results of the statistical analysis using the $\chi^{2}$ -or Fisher’s Exact test showed a significant relationship between TCF4 expression and clinicopathological parameters of epithelial ovarian cancer (Table 2).

3.4 TCF4 expression was associated with age, FIGO stage, lymph node metastasis, intraperitoneal metastasis, intestinal metastasis, vital status, intraperitoneal recurrence, and serum CA153

Using $\chi^{2}$ -or Fisher’s Exact test analysis (Table 2) demonstrated that TCF4 overexpression was correlated with the following clinical characteristics, such as: age ( $P=$ 0.0372); FIGO stage ( $P<$ 0.0001); lymph node metastasis ( $P=$ 0.0172); intraperitoneal metastasis ( $P<$ 0.0001); intestinal metastasis ( $P=$ 0.0002); vital status ( $P=$ 0.0004); intraperitoneal recurrence ( $P=$ 0.0013); and serum CA153 ( $P=$ 0.0081). Moreover, TCF4 expression had no correlation with the following factors, such as: histological type, distant recurrence, residual tumor size, differentiation grade, neoadjuvant chemotherapy, postoperative chemotherapy, platinum resistance, hyperthermic intraperitoneal chemotherapy, ascites with tumor cells ( $+$ ), cytoreductive surgery, serum CA125, CA72-4, AFP, CEA, and HE4 (Table 2). All of these results suggested that TCF4 may play an important role in the development, metastasis, recurrence, and progression of epithelial ovarian cancer.

Table 1, continued
Characteristic	Number of cases (%)
CA125 (U/mL)
$\leqslant$ 35	19 (10.33)
$>$ 35	165 (89.67)
CA72-4 (U/mL)
$\leqslant$ 7	64 (39.75)
$>$ 7	97 (60.25)
CA153 (U/mL)
$\leqslant$ 25	18 (29.51)
$>$ 25	43 (70.49)
AFP (U/mL)
$\leqslant$ 25	149 (98.03)
$>$ 25	3 (1.97)
CEA (U/mL)
$\leqslant$ 5.0	129 (84.31)
$>$ 5.0	24 (15.69)
HE4(pmol/L)
$\leqslant$ 140	37 (32.46)
$>$ 140	77 (67.54)

Table 2
Univariate analysis of TCF4 expression in association with standard clinicopathological variables using the $\chi^{2}$ -or Fisher’s Exact test

Hyperthermic intraperitoneal chemotherapy
Characteristic	Total	TCF4		Chi-squared test	Fisher’s exact test
		No or low expression	Moderate or strong expression	$p$ value	$p$ value
Age (years)
$\leqslant$ 50	94	15	79	0.0372
$>$ 50	94	6	88
Histological type
Serous adenocarcinoma	112	10	102	0.1783
Mucoid adenocarcinoma	11	2	9
Endometrial adenocarcinoma	25	6	19
Clear cell carcinoma	11	1	10
FIGO stage
I	27	8	19		$<$ 0.0001
II	21	8	13
III	110	5	105
IV	30	0	30
Lymph node metastasis
No	51	14	37	0.0172
Yes	32	2	30
Intraperitoneal metastasis
No	60	17	43	$<$ 0.0001
Yes	128	4	124
Intestinal metastasis
No	97	19	78	0.0002
Yes	91	2	89
Vital status
Alive	35	15	20	0.0004
Dead	56	6	50
Intraperitoneal recurrence
No	135	21	114		0.0013
Yes	49	0	49
Distant recurrence
No	161	20	141	0.2546
Yes	23	1	22
Residual tumor size (cm)
$\leqslant$ 1	171	21	150		0.2248
$>$ 1	17	0	17
Differentiation grade
G1/G2	78	13	65	0.0508
G3	97	7	90
Neoadjuvant chemotherapy
No	168	21	147		0.1353
Yes	20	0	20
Postoperative chemotherapy
No	9	2	7	0.2807
Yes	179	19	160
Platinum resistance
No	184	21	163		1.0000
Yes	4	0	4
No	162	19	143	0.5442
Yes	26	2	24
Ascites with tumor cells ( $+$ )
No	43	8	35	0.2467
Yes	41	4	37
Cytoreductive surgery
No	3	0	3		1.0000
Yes	185	21	164
CA125 (U/mL)
$\leqslant$ 35	19	1	18	0.4070
$>$ 35	165	19	146

Table 2, continued
Characteristic	Total	TCF4		Chi-squared test	Fisher’s exact test
		No or low expression	Moderate or strong expression	$p$ value	$p$ value
CA72-4 (U/mL)
$\leqslant$ 7	64	9	55	0.2400
$>$ 7	97	8	89
CA153 (U/mL)
$\leqslant$ 25	18	6	12	0.0081
$>$ 25	43	3	40
AFP (U/mL)
$\leqslant$ 25	149	18	131		1.0000
$>$ 25	3	0	3
CEA (U/mL)
$\leqslant$ 5.0	129	16	113	0.9895
$>$ 5.0	24	3	21
HE4 (U/mL)
$\leqslant$ 140	37	4	33	0.9453
$>$ 140	77	8	69

Table 3

Cox regression univariate and multivariate analyses of prognostic factors in epithelial ovarian cancer

Variable	Univariate analysis			Multivariate analysis
	Number of patients	$p$	Regression coefficient (SE)	$p$	95% Confidence interval
TCF4		0.030	0.480	0.016	1.246–8.710
Low expression	21
High expression	167
Intraperitoneal metastasis		0.035	0.448	0.068	–
No	60
Yes	128
Postoperative chemotherapy		0.017	0.773	0.001	0.013–0.343
No	9
Yes	179
Hyperthermic intraperitoneal chemotherapy		0.009	0.505	0.009	1.402–10.400
No	162
Yes	26

3.5 TCF4 overexpression was significantly related with poor prognosis

Furthermore, we also assessed the prognostic value of TCF4 overexpression in epithelial ovarian cancer patients. In a univariate Cox analysis, TCF4 expression, intraperitoneal metastasis, postoperative chemotherapy, and hyperthermic intraperitoneal chemotherapy were significant prognostic factors (Table 3). In addition, multivariate Cox regression analysis further showed that TCF4 protein expression was an indeed independent prognostic factor of epithelial ovarian cancer (Table 3). Taken together, these results suggested that TCF4 expression was an independent prognostic predictor, and TCF4 may contribute to the prognosis of epithelial ovarian cancer, which suggested that TCF4 may be a useful independent prognostic marker in epithelial ovarian cancer. Moreover, In this multivariate model, intraperitoneal metastasis was no longer significant.

4. Discussions

As we all know, the Wnt/ $\beta$ -catenin signal pathway involves in regulating many important cellular processes, such as cancer development and differentiation, apoptosis, immunologic and inflammatory responses, cell-cycle progression and cellular division [4, 5], and so on. Upon Wnt signaling pathway, $\beta$ -catenin functions as a transcriptional regulator in the nucleus together with TCF4 [10, 11]. And TCF4 is a major component of the Wnt/ $\beta$ -catenin signal pathway. In many cancer cells, TCF4 is localized to the nucleus [12]. Ishiguro et al. reported [13] that nuclear expression of TCF4 is correlated with poor prognosis in patients with esophageal squamous cell carcinoma, and their data suggest that TCF4 alone is located in the nucleus without beta-catenin. In addition, Bleckmann et al. reported that nuclear LEF1/TCF4 correlate with poor prognosis but not with nuclear $\beta$ -catenin in cerebral metastasis of lung adenocarcinomas. But in contrast, in this research our current experiments showed that TCF4 expressed in the cytoplasmic of epithelial ovarian cancer tissues. And our results may reply that TCF4 play its role with the translocation from the nucleus to the cytoplasm in epithelial ovarian cancer cells, thus regulats many important cellular processes, including cancer development and differentiation, cell apoptosis, immunologic and inflammatory responses, cell-cycle progression and cellular division. But the role and mechanism need to be further investigated.

Prior to our research, several clinical studies have reported that TCF4 is an indicator of poor prognosis or malignant potential in hepatocellular carcinomas [14], colon cancer [15], lung adenocarcinomas [16] and esophageal squamous cell carcinoma [13]. And interestingly, consistent with these reports, we found that TCF4 predicted the poor prognosis of patients with epithelial ovarian cancer. And our data for the first time suggested that TCF4 can be used to act as a candidate useful biomarker for predicting prognosis in patients with epithelial ovarian cancer. In this study, we found that patients with high expression of TCF4 had a poorer prognosis.

Moreover, Ishiguro et al. reported [13] that TCF4 expression was correlated with Tumor status, pathological stage, lymphatic invasion and blood vessel invasion, but did not correlate with age, gender or lymph node status. However, in the study overexpression of TCF4 in epithelial ovarian cancer patients was found to be significantly related with age, FIGO stage, lymph node metastasis, intraperitoneal metastasis, intestinal metastasis, vital status, intraperitoneal recurrence, and serum CA153. Thus, we concluded that patients with TCF4 overexpression were more likely to trend for older patients, which indicated that TCF4 detection should be performed in older people in order to diagnose earlier. Moreover, TCF4 overexpression were more in III/IV stages, and this showed that TCF4 overexpression were more likely to exhibit advanced disease, so we concluded that TCF4 expression increased with the occurrence and progress of ovarian cancer. In addition, we found that TCF4 overexpression were more likely to develop lymph node metastasis, intraperitoneal metastasis, and intestinal metastasis, which showed that TCF4 was correlated with ovarian cancer metastasis and migration. Moreover, we found that TCF4 overexpression were more likely to develop intraperitoneal recurrence, which suggested that TCF4 was associated with intraperitoneal recurrence of epithelial ovarian cancer. To the best of our knowledge, epithelial ovarian cancer metastasis and recurrence are the major risk factors of poor survival of patients. Patients with metastasis and recurrence usually have a worse prognosis. Thus, an early diagnosis of intraperitoneal metastasis and recurrence is important for the survival of ovarian cancer patients, but only a few tumor markers are currently used to predict recurrence and metastasis of ovarian cancer in the clinical work. So our data showed that TCF4 is meaningful as a biomarker or predictor to diagnose metastasis and recurrence of ovarian cancer. We concluded that TCF4 may directly or indirectly participate in the migration and invasion of epithelial ovarian cancer. But it need more in viro and in vitro experiments to identify its role in ovarian cancer.

And in a multivariate Cox regression TCF4 was still associated with survival, which showed that TCF4 is a useful indeed independent prognostic marker in ovarian cancer. Taken together, our research showed that TCF4 was associated with the prognosis of epithelial ovarian cancer for the first time.

5. Conclusions

TCF4 may play a candidate oncogenic role in epithelial ovarian cancer, and TCF4 is a useful independent prognostic marker in ovarian cancer, and it may provide a candidate target therapy treatment in future.

Footnotes

Acknowledgments

This work was supported by the Nature Science Fund of Guangdong Province (no.2016A030313536).

Conflict of interest

The authors declare no conflict of interest.

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Expression and clinical significance of transcription factor 4 (TCF4) in epithelial ovarian cancer

Abstract

OBJECTIVES:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Materials and methods

2.1 Paraffin-embedded ovarian cancer tissue samples

3. Results

3.1 Comparison and representative photomicrographs of ovarian cancer/paratumor tissues immunohistochemically stained for TCF4

3.2 TCF4 protein overexpression was associated with disease progression free and overall survival in epithelial ovarian cancer patients

3.3 TCF4 overexpression was correlated with the clinical features of ovarian cancer

Table 1 Clinicopathological parameters and tumor expression of TCF4 in epithelial ovarian cancer

Table 2 Univariate analysis of TCF4 expression in association with standard clinicopathological variables using the χ 2 -or Fisher’s Exact test

4. Discussions

5. Conclusions

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Clinicopathological parameters and tumor expression of TCF4 in epithelial ovarian cancer

Table 2
Univariate analysis of TCF4 expression in association with standard clinicopathological variables using the $\chi^{2}$ -or Fisher’s Exact test