FOXC2 Expression is Associated with Tumor Proliferation and Invasion Potential in Oral Tongue Squamous Cell Carcinoma

Imayama, Naomi; Yamada, Shin‐ichi; Yanamoto, Souichi; Naruse, Tomofumi; Takahashi, Hidenori; Seki, Syûzô; Fujita, Shuichi; Ikeda, Tohru; Umeda, Masahiro

doi:10.1007/s12253-014-9891-6

Cited by 17 publications

(18 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FOXC2 is another important member of FOX gene family that has been reported in many cancers. The overexpression of FOXC2 were found be correlated with poor prognosis of tumor patients and promotes multiple malignant phenotypes of tumor cells, including proliferation, EMT, invasion and stem cell properties [27][28][29][30]. Importantly, the correlations between FOXC2 and tumor chemoresistance are also reported.…”

Section: Discussionmentioning

confidence: 91%

Forkhead Box Protein C2 (FOXC2) Promotes the Resistance of Human Ovarian Cancer Cells to Cisplatin In Vitro and In Vivo

Ding

Tian

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: FOXC2 has been reported to play a role in tumor progression, but the correlations of FOXC2 with the cisplatin (CDDP) resistance of ovarian cancer cells are still unclear. The purpose of the present study is to investigate the roles of FOXC2 in the CDDP resistance of ovarian cancer cells and its possible mechanisms. Methods: Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of FOXC2 mRNA in CDDP-resistant or sensitive ovarian cancer tissues and cell lines (SKOV3/CDDP and SKOV3). Gain- and loss-of-function assays were performed to analyze the effects of FOXC2 knockdown or overexpression on the in vitro and in vivo sensitivity of ovarian cancer cells to CDDP and its possible molecular mechanisms. Results: The relative expression level of FOXC2 mRNA in CDDP-resistant ovarian cancer tissues was higher than that in CDDP-sensitive tissues. Also, the expression of FOXC2 mRNA and protein in CDDP-resistant ovarian cancer cell line (SKOV3/CDDP) cell line was higher than that in its parental cell line (SOKV3). Small hairpin RNA (shRNA)-mediated FOXC2 knockdown significantly increased the in vitro and in vive sensitivity of SKOV3/CDDP cells to CDDP by enhancing apoptosis, while upregulation of FOXC2 significantly decreased the in vitro and in vivo sensitivity of SKOV3 cells to CDDP by reducing apoptosis. Furthermore, FOXC2 activates the Akt and MAPK signaling pathways, and then induced the decreased expression of Bcl-2 protein and the increased expression of Bax and cleaved caspase-3 proteins. Conclusions: FOXC2 mediates the CDDP resistance of ovarian cancer cells by activation of the Akt and MAPK signaling pathways, and may be a potential novel therapeutic target for overcoming CDDP resistance in human ovarian cancer.

show abstract

Section: Discussionmentioning

confidence: 91%

Forkhead Box Protein C2 (FOXC2) Promotes the Resistance of Human Ovarian Cancer Cells to Cisplatin In Vitro and In Vivo

Ding

Tian

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…FOXC2, an important member of FOX family, has been reported to be overexpressed in a variety of human cancer, including colorectal cancer, esophageal cancer, gastric cancer, and so on [42][43][44]. The overexpression of FOXC2 has been found to be correlated with poor prognosis of patients and promotes proliferation, EMT and metastasis of tumor cells [45,46]. Previously, we have shown that FOXC2 could promote the CDDP resistant of ovarian cancer cells by reduction of CDDP-inducing apoptosis [16].…”

Section: Discussionmentioning

confidence: 99%

Forkhead Box Protein C2 Promotes Epithelial-Mesenchymal Transition, Migration and Invasion in Cisplatin-Resistant Human Ovarian Cancer Cell Line (SKOV3/CDDP)

Ding

Tian

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Forkhead Box Protein C2 (FOXC2) has been reported to be overexpressed in a variety of human cancers. However, it is unclear whether FOXC2 regulates epithelial-mesenchymal transition (EMT) in CDDP-resistant ovarian cancer cells. The aim of this study is to investigate the effects of FOXC2 on EMT and invasive characteristics of CDDP-resistant ovarian cancer cells and the underlying molecular mechanism. Methods: MTT, Western blot, scratch wound healing, matrigel transwell invasion, attachment and detachment assays were performed to detect half maximal inhibitory concentration (IC₅₀) of CDDP, expression of EMT-related proteins and invasive characteristics in CDDP-resistant ovarian cancer cell line (SKOV3/CDDP) and its parental cell line (SKOV3). Small hairpin RNA (shRNA) was used to knockdown FOXC2 and analyze the effect of FOXC2 knockdown on EMT and invasive characteristics of SKOV3/CDDP cells. Also, the effect of FOXC2 upregulation on EMT and invasive characteristics of SKOV3 cells was analyzed. Furthermore, the molecular mechanism underlying FOXC2-regulating EMT in ovarian cancer cells was determined. Results: Compared with parental SKOV3 cell line, SKOV3/CDDP showed higher IC₅₀ of CDDP (43.26μM) (P<0.01) and acquired EMT phenotype and invasive characteristics. Gain- and loss-of-function assays indicated that shRNA-mediated FOXC2 knockdown could reverse EMT and reduce the capacity of migration, invasion, attachment and detachment in SKOV3/CDDP cell line and upregulation of FOXC2 could induce the reverse effects in parental SKOV3 cell line. Furthermore, it was found that activation of ERK or AKT/GSK-3β signaling pathways was involved in FOXC2-promoting EMT in CDDP-resistant ovarian cancer cells. Conclusions: Taken together, these data demonstrate that FOXC2 may be a promoter of EMT phenotype in CDDP-resistant ovarian cancer cells and a potential therapeutic target for the treatment of advanced ovarian cancer.

show abstract

“…FOXC2 has been introduced as a mediator of mesenchymal differentiation in the course of EMT, downstream of TGFβ and other EMT‐regulators, and identified as a decisive factor for carcinoma dissemination in breast cancer models . Increased expression of FOXC2 has been linked to oestrogen receptor negative basal‐like breast carcinoma and survival in various cancer types , but survival data for FOXC2 has not yet been presented in prostate cancer. A majority of clinically localised Gleason score 7 cancers are placed in the intermediate risk group (European Association of Urology 2017 ), a large and heterogeneous group of prostate cancers comprising Gleason grade groups 2 and 3.…”

Section: Discussionmentioning

confidence: 99%

“…Up‐regulation of FOXC2 has been associated with progression and poor prognosis in various malignancies such as lung , colon , gastric , oral tongue squamous cell carcinoma and hepatocellular carcinomas . However, there are still no available survival data on FOXC2 in prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

FOXC2 expression and epithelial–mesenchymal phenotypes are associated with castration resistance, metastasis and survival in prostate cancer

Børretzen

Gravdal

Haukaas

et al. 2019

The Journal of Pathology CR

View full text Add to dashboard Cite

Epithelial–mesenchymal transition (EMT) is important for tumour cell invasion and metastasis and is a feature of aggressive carcinomas. EMT is characterised by reduced E‐cadherin and increased N‐cadherin expression (EN‐switch), and increased expression of the EMT‐regulating transcription factor Forkhead box protein C2 (FOXC2) has been associated with progression and poor prognosis in various malignancies. FOXC2 was recently highlighted as a novel therapy target in prostate cancer, but survival data on FOXC2 are lacking. This study evaluates the expression of FOXC2, E‐cadherin and N‐cadherin in different prostatic tissues focusing on EMT, clinico‐pathological phenotype, recurrence and patient survival. Tissue microarray sections from 338 radical prostatectomies (1986–2007) with long and complete follow‐up, 33 castration resistant prostate cancers, 33 non‐skeletal metastases, 13 skeletal metastases and 41 prostatic hyperplasias were stained immunohistochemically for FOXC2, E‐cadherin and N‐cadherin. FOXC2 was strongly expressed in primary carcinomas, including castration resistant tumours and metastatic lesions as compared to benign prostatic hyperplasia. A hybrid epithelial–mesenchymal phenotype, with co‐expression of E‐cadherin and N‐cadherin, was found in the majority of skeletal metastases and in a substantial proportion of castration resistant tumours. In localised carcinomas, the EN‐switch was associated with adverse clinico‐pathological variables, such as extra‐prostatic extension, high pathological stage and lymph node infiltration. In univariate survival analyses of the clinically important, large subgroup of 199 patients with Gleason score 7, high FOXC2 expression and EN‐switching were significantly associated with shorter time to clinical recurrence, skeletal metastases and cancer specific death. In multivariate Cox' survival analysis, high FOXC2 and the EN‐switch, together with Gleason grade group (GG3 versus GG2), were independent predictors of time to these end‐points. High FOXC2 gene expression (mRNA) was also related to patient outcome, validating our immunohistochemical findings. FOXC2 and factors signifying EMT or its intermediate states may prove important as biomarkers for aggressive disease and are potential novel therapy targets in prostate cancer.

show abstract

FOXC2 Expression is Associated with Tumor Proliferation and Invasion Potential in Oral Tongue Squamous Cell Carcinoma

Cited by 17 publications

References 36 publications

Forkhead Box Protein C2 (FOXC2) Promotes the Resistance of Human Ovarian Cancer Cells to Cisplatin In Vitro and In Vivo

Forkhead Box Protein C2 (FOXC2) Promotes the Resistance of Human Ovarian Cancer Cells to Cisplatin In Vitro and In Vivo

Forkhead Box Protein C2 Promotes Epithelial-Mesenchymal Transition, Migration and Invasion in Cisplatin-Resistant Human Ovarian Cancer Cell Line (SKOV3/CDDP)

FOXC2 expression and epithelial–mesenchymal phenotypes are associated with castration resistance, metastasis and survival in prostate cancer

Contact Info

Product

Resources

About