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Abstract

OBJECTIVE:

To investigate FOXO1 expression in epithelial ovarian cancer (EOC), and to explore its correlation with clinicopathological parameters and prognosis of EOC.

METHODS:

Two hundred and sixteen cases of paraffin-embedded EOC and 41 paratumor tissues from 2009 to 2017 that had been pathologically confirmed at the memorial hospital of Sun Yat-sen University were included in this study, and the expression of FOXO1 was performed by immunohistochemistry using a polyclonal antibody specific for FOXO1.

RESULTS:

FOXO1 protein expression is associated with Recurrence free and overall survival in EOC patients; In addition, FOXO1 expression is associated with age, FIGO stage, intraperitoneal metastasis, intestinal metastasis, vital status, intraperitoneal recurrence and differentiation grade; Moreover, in a multivariate model FOXO1 overexpression was an independent predictor of poor survival in EOC.

CONCLUSION:

FOXO1 may play a candidate oncogenic role in EOC, and FOXO1 is a useful independent prognostic marker in EOC, and it may provide a candidate target therapy in future.

Keywords

FOXO1 epithelial ovarian cancer prognosis

1. Background

Ovarian cancer is the first leading cause of death from cancers of the female reproductive system [1]. Each year, approximately 238,700 patients are diagnosed with this disease and approximately 151,900 associated mortalities occur globally [2]. And the most type is epithelial. Most of EOC is diagnosed at an advanced stage (the International Federation of Gynecology and Obstetrics (FIGO) III or IV stages) because of the lack of specific symptoms and the absence of effective early diagnostic methods, which leads to a poor prognosis [1, 3]. Recently serum biomarkers such as CA125 and HE4 have been used to monitor the progress and prognosis of ovarian cancer, and also to detect the recurrence of disease after operation or chemotherapy. However, these biomarkers are neither extremely sensitive nor particularly specific for predicting cancer metastasis, recurrence, and prognosis. Therefore, further studies to search new biomarkers and to provide targeted therapy are very important.

The FOXO1 gene located on chromosome 13q4 in human, which is a member of the forkhead box (FOXO) family, and ther are a series of recent studies have demonstrated plays an important role in several intracellular functions, including autophagy [4, 5], cell cycle [6], apoptosis [7], and tumor suppression [8]. Moreover, Many researches have reported that FOXO1 has antineoplastic actions in digestive system cancers [9, 10, 11, 12, 13], prostate cancer [14], breast cancer [15], hematological cancer [16] and others [17, 18]. But in contrary, FOXO1 plays an opposite role in acute myeloid leukemia [19] and renal cell carcinoma [20]. However, there have been no research about the role of FOXO1 in EOC already. Therefore, in this research we aimed to investigate the FOXO1 expression in EOC tissues and paratumor tissues, and to study its clinicopathological and prognostic correlations in EOC.

2. Material and methods

2.1 Tissue specimens

A total of 216 paraffin-embedded ovarian cancer and 41 paratumor tissues from 2009 to 2017 that had been pathologically confirmed at the memorial hospital of Sun Yat-sen University were included in this study. Survival duration was calculated from the operation date until 14 April 2018 when any remaining survivors were included. This trial was obtained approval from the memorial hospital of Sun Yat-sen University Ethics Committee.

2.2 Immunohistochemistry (IHC)

The FOXO1 protein expression levels in the human EOC tissues were detected by immunohistochemistry. Briefly, 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. Next, high tension was used for antigen retrieval, and the specimens were treated with 3% hydrogen peroxide in methanol to quench endogenous peroxidase activity, followed by incubation with 1% bovine serum albumin to block nonspecific binding, and incubation with anti-rabbit FOXO1 polyclonal antibodies (1:150; proteitech) at 4 ${{}^{\circ}}$ C overnight. After washing, the tissue sections were treated with anti-rabbit secondary antibody (Sigma), then incubated with streptavidin horseradish peroxidase complex (Sigma), immersed in 3-amino-9-ethyl carbazole. 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, paraffin-embedded section. The score was due to both the proportion of positively stained tumor 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 absent 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 cancer 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 FOXO1 expression, and a staining score of $\leqslant$ 5 indicated low FOXO1 expression [21, 22].

Figure 1.

FOXO1 expression in EOC tissues and paratumor tissues (scale bar: 25 $\mu$ m).

Figure 2.

The different straining of FOXO1 expression in EOC (scale bar: 25 $\mu$ m).

Figure 3.

Kaplan-Meier survival of overall survival (OS) and Recurrence free survival (RFS) in dead EOC patients: A. Kaplan-Meier survival of overall survival (OS) in dead ovarian cancer patients; B. Kaplan-Meier survival of Recurrence free survival (RFS) in dead ovarian cancer patients.

2.3 Statistical analysis

All of the statistical analyses were carried out with the statistical software package SPSS 21.0. The chi-square and Fisher’s exact test were used to analyze the relationship between FOXO1 protein expression levels and clinicopathological characteristics. Additionally, bivariate correlations were computed by Spearman’s rank correlation coefficients. Patient survival was determined by a Kaplan-Meier analysis, and the differences were counted by the log-rank test. Cox’s proportional hazards regression model was applied to the multivariate analysis. A $p$ value of $<$ 0.05 in all of the analyses was considered statistically significant.

3. Results

3.1 FOXO1 protein expression is associated with Recurrence free survival and overall survival in EOC patients

To determine whether the FOXO1 protein expression was associated with EOC patients survival, we stained 216 EOC cases and 41 paired paratumor tissues using IHC with a rabbit polyclonal antibody specific for FOXO1. We found that FOXO1 expression staining located at cytoplasmic (Fig. 1).

Moreover, in the 216 evaluable EOC tissues stained, 31/216 (14.4%) had absent/weak staining (also called low expression) and 185/216 (85.6%) had moderate/ strong staining (also called high expression) (Fig. 2).

In addition, Kaplan-Meier survival analysis demonstrated that there was a statistically significance on Recurrence free survival (RFS) between high and low expression of FOXO1 ( $p<$ 0.001). Moreover, there was also a statistically significant difference on overall survival ( $p=$ 0.004) (Fig. 3). A survival analysis revealed that the cumulative overall survival (OS) and Recurrence free survival (RFS) rates of EOC patients decreased with increasing in FOXO1 protein expression.

3.2 Comparison of EOC/paratumor tissues immunohistochemically stained for FOXO1

In 216 EOC tissues stained with the specific FOXO1 antibody, 31/216 (14.4%) had weak/absent staining and 185/216 (85.6%) had strong/moderate staining, while in 41 ovarian paratumor tissues stained with the FOXO1 specific antibody, 35/41 (85.4%) had absent/weak staining and 6/41 (14.6%) had moderate/ strong staining, and there was significantly different between cancer and paratumor groups ( $p<$ 0.001) (Fig. 4).

Figure 4.

The comparison of FOXO1 expression between tumor and paratumor tissues.

Table 1

Clinicopathological characteristics and FOXO1 expression in EOC

Characteristic	Number of cases (%)
Age (years)
$\leqslant$ 50	97	(44.9)
$>$ 50	119	(55.1)
FIGO stage
I	35	(16.2)
II	25	(11.6)
III	123	(56.9)
IV	33	(15.3)
Histological type
Serous adenocarcinoma	131	(70.1)
Mucoid adenocarcinoma	8	(4.3)
Endometrial adenocarcinoma	31	(16.6)
Clear cell carcinoma	17	(9.0)
Lymph node metastasis
Absent	61	(63.5)
Present	35	(36.5)
Intraperitoneal metastasis
No	72	(33.5)
Yes	143	(66.5)
Intestinal metastasis
No	115	(53.5)
Yes	100	(46.5)
Expression of FOXO1
Low or none	31	(14.4)
Moderate or high	185	(85.6)
Vital status (at last follow-up)
Alive	92	(53.8)
Dead	79	(46.2)
Intraperitoneal recurrence
No	157	(74.8)
Yes	53	(25.2)
Distant recurrence
No	183	(87.1)
Yes	27	(12.9)
Residual tumor size (cm)
$\leqslant$ 1	199	(92.1)
$>$ 1	17	(7.9)
Differentiation grade
G1/G2	89	(45.6)
G3	106	(54.4)

Table 1, continued
Characteristic	Number of cases (%)
Neoadjuvant chemotherapy
No	190	(88.0)
Yes	26	(12.0)
Postoperative chemotherapy
No	9	(4.2)
Yes	205	(95.8)
Hyperthermic intraperitoneal chemotherapy
No	195	(90.3)
Yes	21	(9.7)
Ascites see tumor cells ( $+$ )
No	49	(52.1)
Yes	45	(47.9)
Cytoreductive surgery
No	5	(2.3)
Yes	211	(97.7)
Platinum resistance
No	210	(97.2)
Yes	6	(2.8)
CA125 (U/mL)
$\leqslant$ 35	31	(14.4)
$>$ 35	184	(85.6)
CA72-4 (U/mL)
$\leqslant$ 7	87	(46.3)
$>$ 7	101	(53.7)
CA153 (U/mL)
$\leqslant$ 25	24	(29.6)
$>$ 25	57	(70.4)
AFP (U/mL)
$\leqslant$ 25	175	(97.8)
$>$ 25	4	(2.2)
CEA (U/mL)
$\leqslant$ 5.0	161	(89.0)
$>$ 5.0	20	(11.0)
HE4 (pmol/L)
$\leqslant$ 140	37	(32.5)
$>$ 140	77	(67.5)

3.3 FOXO1 overexpression was related with the clinical parameters of ovarian cancer

Subsequently, we studied its correlation with the clinical parameters of EOC. The percentage of patients with stages I–IV tumors were 16.2%, 11.6%, 56.9%, and 15.3%, respectively (Table 1). In this study, patients with high expression of FOXO1 exhibited a median overall survial time of 20 months, while patients with low expression of FOXO1 exhibited a median overall survial time of 36 months. Moreover, patients with high expression of FOXO1 exhibited a median Recurrence free survial time of 9 months, while patients with low expression of FOXO1 exhibited a median Recurrence free survial time of 30 months.

In addition, The results of $\chi^{2}$ or Fisher’s Exact test revealed a significant relationship between FOXO1 protein expression and clinicopathological parameters of EOC, such as the following factors: histological type, FIGO stage, lymph node metastasis, intraperitoneal metastasis, intestinal metastasis, vital status (at last follow-up), intraperitoneal recurrence, distant recurrence, hyperthermic intraperitoneal chemotherapy, and so on (Table 2).

Table 2
FOXO1 expression in association with standard clinicopathological variables using the $\chi^{2}$ or Fisher’s Exact test

Characteristic		Total	No or weak expression	Moderate or strong expression	Chi-squared test $p$ value	Fisher’s Exact test $p$ value
			FOXO1
Age (years)	$\leqslant$ 50	97	15	82	0.674
	$>$ 50	119	16	103
Histological type	Serous adenocarcinoma	131	12	119		0.0015
	Mucoid adenocarcinoma	8	4	4
	Endometrial adenocarcinoma	31	7	24
	Clear cell carcinoma	17	5	12
FIGO stage	I	35	16	19		$<$ 0.001
	II	25	4	21
	III	123	10	113
	IV	33	1	32
Lymph node metastasis	No	61	15	46	0.025
	Yes	35	2	33
Intraperitoneal metastasis	No	72	20	52	$<$ 0.001
	Yes	143	10	133
Intestinal metastasis	No	115	26	89	$<$ 0.001
	Yes	100	4	96
Vital status	Alive	92	20	72	0.0408
	Dead	79	8	71
Intraperitoneal recurrence	No	157	29	128	0.0013
	Yes	53	1	52
Distant recurrence	No	183	30	153	0.0173
	Yes	27	0	27
Residual tumor size (cm)	$\leqslant$ 1	199	30	169	0.478
	$>$ 1	17	1	16
Differentiation grade	G1/G2	89	12	77	0.955
	G3	106	14	92
Neoadjuvant chemotherapy	No	190	30	160	0.138
	Yes	26	1	25
Postoperative chemotherapy	No	9	0	9	0.363
	Yes	205	31	174
Platinum resistance	No	210	31	179	0.597
	Yes	6	0	6
Hyperthermic intraperitoneal	No	195	31	164	0.049
chemotherapy	Yes	21	0	21
Ascites with tumor cells ( $+$ )	No	49	8	41	0.464
	Yes	45	5	40
Cytoreductive surgery	No	5	2	3		0.151
	Yes	211	29	182
CA125 (U/mL)	$\leqslant$ 35	31	6	25	0.348
	$>$ 35	184	24	160
CA72-4 (U/mL)	$\leqslant$ 7	87	15	72	0.796
	$>$ 7	101	16	85
CA153 (U/mL)	$\leqslant$ 25	24	3	21	$>$ 0.999
	$>$ 25	57	7	50
AFP (U/mL)	$\leqslant$ 25	175	25	150		$>$ 0.999
	$>$ 25	4	0	4
CEA (U/mL)	$\leqslant$ 5.0	161	21	140	0.151
	$>$ 5.0	20	5	15
HE4 (U/mL)	$\leqslant$ 140	37	9	28	0.187
	$>$ 140	77	11	66

Table 3

Correlation between FOXO1 expression and clinicopathological characteristics of EOC

Variable	FOXO1 expression
	Spearman’s correlation coefficient	$p$ value
Age	0.158	0.020
Histological type	$-$ 0.058	0.396
FIGO stage	0.281	$<$ 0.001
Intraperitoneal metastasis	0.243	$<$ 0.001
Lymph node metastasis	0.201	0.050
Intestinal metastasis	0.278	$<$ 0.001
Vital status (at last follow-up)	0.168	0.022
Intraperitoneal recurrence	0.165	0.017
Distant recurrence	0.117	0.090
Residual tumor size (cm)	0.050	0.465
Differentiation grade	0.234	0.001
Neoadjuvant chemotherapy	$-$ 0.020	0.769
Postoperative chemotherapy	0.004	0.952
Hyperthermic intraperitoneal chemotherapy	0.102	0.137
Ascites with tumor cells	$-$ 0.054	0.610
Cytoreductive surgery	$-$ 0.062	0.368
Platinum resistance	$-$ 0.057	0.402
CA125 (U/mL)	0.109	0.112
CA724 (U/mL)	0.079	0.281
CA153 (U/mL)	$-$ 0.044	0.696
AFP (U/mL)	$-$ 0.03	0.972
CEA (U/mL)	0.057	0.447
HE4	0.064	0.502

Table 4

Cox regression univariate and multivariate analyses of prognostic factors in EOC

Variable	Univariate analysis			Multivariate analysis
	Number of patients	$p$	Regression coefficient (SE)	$p$	95% Confidence interval
FOXO1		0.008	0.404	0.024	1.131–5.917
Low expression	31
High expression	185
Histological type		0.014	0.073	0.033	1.012–1.345
Serous adenocarcinoma	131
Mucoid adenocarcinoma	8
Endometrial adenocarcinoma	31
Clear cell carcinoma	17
Intestinal metastasis		0.022	0.262	0.369	0.744–2.213
No	115
Yes	100
Hyperthermic intraperitoneal chemotherapy		0.003	0.424	0.020	1.173–6.380
No	195
Yes	21

3.4 FOXO1 expression is associated with Age, FIGO stage, intraperitoneal metastasis, intestinal metastasis, vital status, intraperitoneal recurrence and differentiation grade

Spearman’s correlation analysis revealed that high FOXO1 expression was correlated with the following clinical characteristics: age ( $p=$ 0.020), FIGO stage ( $p<$ 0.001), intraperitoneal metastasis ( $p<$ 0.001), intestinal metastasis ( $p<$ 0.001), vital status ( $p=$ 0.022), intraperitoneal recurrence ( $p=$ 0.017), and differentiation grade ( $p=$ 0.001) (Table 3). In contrast, FOXO1 expression had no correlation with the following factors, such as: histological type, lymph node metastasis, distant recurrence, residual tumor size, neoadjuvant chemotherapy, postoperative chemotherapy, hyperthermic intraperitoneal chemotherapy, ascites with tumor cells, cytoreductive surgery, platinum resistance, serum CA125, CA724, CA153, AFP, CEA and HE4 (Table 3). All of these results suggest that FOXO1 may play an important role in cancer development of EOC.

3.5 FOXO1 overexpression was significantly associated with a poor prognosis

Furthermore, we also assessed the prognostic value of FOXO1 expression in EOC patient. In a univariate Cox analysis, FOXO1 expression, histological type, intestinal metastasis, hyperthermic intraperitoneal chemotherapy were significant prognostic factors (Table 4). Moreover, in a multivariate Cox regression analysis found that FOXO1 expression, histological type and hyperthermic intraperitoneal chemotherapy were indeed independent prognostic factors of EOC (Table 4), but intestinal metastasis was no longer significant. Taken together, all of these results suggest that FOXO1 expression was an indeed independent prognostic factor, and FOXO1 overexpression may corelate with the prognosis of EOC.

4. Discussion

Many studies have showed that FOXO1 has antineoplastic actions in a great deal of different cancers [23], such as: digestive system cancers [9, 10, 11, 12, 13], prostate cancer [14], breast cancer [15], hematological cancer [16] and others [17, 18]. But in contrary, FOXO1 plays an opposite role in acute myeloid leukemia [19] and renal cell carcinoma [20]. So there have been some disputes on its negative or positive role in tumors. In this study we for the first time demonstrated that FOXO1 protein expression was elevated in EOC tissues, and in 216 EOC tissues, 185/216 (85.6%) had strong/moderate staining, while only 6/41 (14.6%) had strong/moderate staining in paratumor group, which suggested that FOXO1 may play a candidate oncogenic role in EOC.

Moreover, overexpression of FOXO1 in EOC patients was found to be significantly related with age, FIGO stage, intraperitoneal metastasis, intestinal metastasis, vital status (at last follow-up), intraperitoneal recurrence and differentiation grade. Thus, we concluded that patients with FOXO1 overexpression was more likely to trend for older patients, and this indicated that FOXO1 detection should performed in older people in order to diagnose earlier. Moreover, FOXO1 overexpression was more in stage III/IV patients than that in stage I/II patients, and FOXO1 overexpression was more in grade G3 patients than that in grade G1/G2 patients, and these results showed that FOXO1 overexpression were more likely to exhibit advanced and high grade disease, so we concluded that FOXO1 expression increased with the initiation and progress of ovarian cancer, and it could be recommended as a candidate molecular biomarker.

In addition, FOXO1 overexpression was more likely to exhibit intraperitoneal metastasis, intestinal metastasis and intraperitoneal recurrence, and all of these results showed that FOXO1 was correlated with EOC metastasis and recurrence. To the best of our knowledge, ovarian cancer metastasis and recurrence are the major risk factors of poor survival. 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. However, only a few tumor markers are currently used to predict intraperitoneal metastasis in the clinical work. And according to our results, FOXO1 overexpression was associated with intraperitoneal metastasis and recurrence, and it was meaningful as a biomarker or predictor to diagnose intraperitoneal metastasis and recurrence. Moreover, we concluded that FOXO1 may directly or indirectly involve in the migration and invasion of EOC. And it needs more in vivo and in vitro experiments to identify its role in ovarian cancer.

More importantly, our results showed that FOXO1 overexpression has a poor overall survival (OS) and Recurrence free survival (RFS) of EOC patients. And a survival analysis revealed that the cumulative OS and RFS rates of EOC patients increased with increase in FOXO1 protein expression. In this study, patients with high FOXO1 expression exhibited a median overall survival time of only 20 months and a median RFS time of only 9 months, while these values in patients with low FOXO1 expression were 36 and 30 months, respectively. And in a multivariate Cox regression analysis we found that FOXO1 expression, histological type, and hyperthermic intraperitoneal chemotherapy were indeed independent prognostic factors of ovarian cancer, but intestinal metastasis was no longer significant, which suggest that hyperthermic intraperitoneal chemotherapy should be performed in cytoreductive surgery, because it influences the prognosis of ovarian cancer.

In conclusion, all of these results suggest that FOXO1 overexpression is an independent prognostic factor, and FOXO1 overexpression may corelate with the progression and poor prognosis of EOC. In future, we need more in vivo and in vitro study to demonstrate its role and molecular mechanism in development and progression of EOC.

5. Conclusions

In short, we demonstrated that FOXO1 overexpression is an independent prognostic factor, and FOXO1 is a useful independent prognostic marker in EOC for the first time. In future, we need more in vivo and in vitro study to demonstrate its role and molecular mechanism in development and progression of EOC.

Footnotes

Acknowledgments

We would like to thank all the participants that contribute to this work. This study was supported by the Guangdong Provincial Medical Research Fund (grant no. A2019096), the President funds of Integrated Hospital of Traditional Chinese Medicine, Southern Medical University (No. 1201902001; No. 1201901002), the High-Level Academic Talent Training Program of Guangzhou Medical University (No. B185004083; No. B195001100), Guangzhou Science and Information Bureau Item (grant no. 201904010013), Natural Science Foundation of Guangdong Province (grant no. 2018A0303130 180) and Hospital achievement transformation and Cultivation Project (grant no. ZH201812).

Conflict of interest

The authors declare no conflict of interest.

References

Chen

Zheng

Baade

P.D.

et al., Cancer statistics in China, 2015, CA. Cancer J. Clin. 66(2) (2016), 115–132.

Liu

Zeng

et al., Expression and clinical significance of transcription factor 4 (TCF4) in epithelial ovarian cancer, Cancer Biomark 24(2) (2019), 213–221.

Jayson

G.C.

Kohn

E.C.

Kitchener

H.C.

et al., Ovarian cancer, Lancet 384 (2014), 1376–1388. doi: 10.1016/S0140-6736(13)62146-7.

Zhang

et al., FOXO1, a potential therapeutic target, regulates autophagic flux, oxidative stress, mitochondrial dysfunction, and apoptosis in human cholangiocarcinoma QBC939 cells, Cell Physiol Biochem 45(4) (2018), 1506–1514.

Wang

Ding

Zhang

et al., Role of FOXO1 in aldosterone-induced autophagy: A compensatory protective mechanism related to podocyte injury, Oncotarget 7(29) (2016), 45331–45351.

Jash

and Puri

, FoxO1-autophagy axis regulates lipid droplet growth via FSP27, Cell Cycle 15 (2016), 2856–2857.

Chi

H.C.

Chen

S.L.

Cheng

Y.H.

et al., Chemotherapy resistance and metastasis-promoting effects of thyroid hormone in hepatocarcinoma cells are mediated by suppression of FoxO1 and Bim pathway, Cell Death Dis 7 (2016), e2324.

C.F.

Zhang

W.G.

Liu

et al., Aquaporin 9 inhibits hepatocellular carcinoma through up-regulating FOXO1 expression, Oncotarget 7 (2016), 44161–44170.

Weigel

Jurgens

Kuttner

et al., The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo, Cell 57 (1989), 645–658.

10.

Weigel

and Jackle

, The fork head domain: A novel DNA binding motif of eukaryotic transcription factors? Cell 63 (1990), 455–456.

11.

Frampton

Invernizzi

Bernuzzi

et al., Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism, Gut 61 (2012), 268–277.

12.

Boreddy

S.R.

Pramanik

K.C.

and Srivastava

S.K.

, Pancreatic tumor suppression by benzyl isothiocyanate is associated with inhibition of PI3K/AKT/FOXO pathway, Clin Cancer Res 17 (2011), 1784–1795.

13.

Urban

B.C.

Collard

T.J.

Eagle

C.J.

et al., BCL-3 expression promotes colorectal tumorigenesis through activation of AKT signalling, Gut 65 (2016), 1151–1164.

14.

Zhang

Pan

Zheng

et al., FOXO1 inhibits Runx2 transcriptional activity and prostate cancer cell migration and invasion, Cancer Res 71 (2011), 3257–3267.

15.

W.K.

Cho

K.B.

Hien

T.T.

et al., Amurensin G, a potent natural SIRT1 inhibitor, rescues doxorubicin responsiveness via down-regulation of multidrug resistance 1, Mol Pharmacol 78 (2010), 855–864.

16.

Xie

Ushmorov

Leithauser

et al., FOXO1 is a tumor suppressor in classical hodgkin lymphoma, Blood 119 (2012), 3503–3511.

17.

Z.H.

Shun

W.W.

Hang

J.B.

et al., Posttranslational modifications of FOXO1 regulate epidermal growth factor receptor tyrosine kinase inhibitor resistance for nonâ€small cell lung cancer cells, Tumor Biol 36 (2015), 5485–5495.

18.

Yang

Liang

Yang

et al., Propofol inhibits lung cancer cell viability and induces cell apoptosis by upregulating microRNA-486 expression, Braz J Med Biol Res 50 (2017), e5794.

19.

Kode

Mosialou

Manavalan

S.J.

et al., FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice, Leukemia 30 (2016), 1–13.

20.

Lin

Piao

H.L.

Zhuang

et al., FoxO transcription factors promote AKT Ser473 phosphorylation and renal tumor growth in response to pharmacologic inhibition of the PI3K-AKT pathway, Cancer Res 74 (2014), 1682–1693.

21.

Liu

Deng

et al., MYH9 overexpression correlates with clinicopathological parameters and poor prognosis of epithelial ovarian cancer, Oncol Lett 18(4) (2019), 1049–1056.

22.

Yao

Liu

et al., Low expression of KIF7 indicates poor prognosis in epithelial ovarian cancer, Cancer Biomark (2019 Oct 18). doi: 10.3233/CBM-190328.

23.

Jiang

Yang

et al., Deciphering the roles of FOXO1 in human neoplasms, Int J Cancer (2018 Feb 23). doi: 10.1002/ijc.31338.

FOXO1 overexpression is correlated with poor prognosis in epithelial ovarian cancer

Abstract

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Background

2. Material and methods

2.1 Tissue specimens

2.2 Immunohistochemistry (IHC)

3. Results

3.1 FOXO1 protein expression is associated with Recurrence free survival and overall survival in EOC patients

3.2 Comparison of EOC/paratumor tissues immunohistochemically stained for FOXO1

Table 2 FOXO1 expression in association with standard clinicopathological variables using the χ 2 or Fisher’s Exact test

3.5 FOXO1 overexpression was significantly associated with a poor prognosis

4. Discussion

5. Conclusions

Footnotes

Acknowledgments

Conflict of interest

References

Table 2
FOXO1 expression in association with standard clinicopathological variables using the $\chi^{2}$ or Fisher’s Exact test