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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 347-353

Keratinocyte growth factor binding to fibroblast growth factor receptor 2-IIIb promotes epithelial ovarian cancer cell proliferation and invasion


1 Department of Pathology, College of Basic Medicine, Harbin Medical University; Department of Thoracic Surgery Esophageal Mediastinum, Affiliated Tumor Hospital of Harbin Medical University, Harbin 150081, Heilongjiang, China
2 Department of Pathology, Affiliated First Hospital of Harbin Medical University, Harbin 150081, Heilongjiang, China
3 Department of Pathology, College of Basic Medicine, Harbin Medical University, Harbin 150081, Heilongjiang, China
4 Department of Pathology, Affiliated Second Hospital, Mudanjiang Medical College, Mudanjiang 157009, Heilongjiang, China
5 Department of Medical Genetics Key Laboratory of Medical Genetics, Harbin Medical University, Heilongjiang Higher Education Institutions, Harbin 150081, Heilongjiang, China
6 Department of Statistical Genetics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, Heilongjiang, China

Date of Web Publication29-Jun-2018

Correspondence Address:
He Chen
Department of Pathology, College of Basic Medicine, Harbin Medical University, Harbin 150081, Heilongjiang
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.235353

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 > Abstract 

Aim of Study: To analyze the function of keratinocyte growth factor (KGF) and it ligand fibroblast growth factor receptor 2-IIIb (FGFR2-IIIb) in the epithelial ovarian cancer (EOC) progression.
Materials and Methods: In this study, the protein KGF and corresponding ligand FGFR2-IIIb expression were detected in both normal epithelial ovarian tissues and in EOC tissues. Seventy-one ovarian tumor tissues were examined for KGF and FGFR2-IIIb expression by immunohistochemistry; seven normal epithelial ovarian tissues as control were examined. By using a monoclonal antibody to inhibit KGF activation, we tested KGF-induced EOC cells invasion ability. By means of Western blot, we tested extracellular signal-regulated kinase (ERK), phosphorylation ERK, myosin light chain (MLC), and phosphorylation MLC with or without KGF protein.
Results: We found that the expression FGFR2-IIIb increased in EOC cells and tissues comparing with its normal counterpart, and the expression of KGF protein decreased or undetectable in human EOC cells and tissues comparing with its normal part. The effect of KGF in promoting EOC cell invasion was blocked by an FGFR2-IIIb antibody. We further discovered that KGF upregulated ERK and MLC phosphorylation in the highly invasive ovarian cancer cell line HO8910PM. Therefore, regarding the highly invasive ovarian cancer cells, we speculated that KGF might promote proliferation and invasion through the ERK-MLC pathway.
Conclusions: These results suggest that KGF might play an important role in the progression of ovarian cancer and could be an attractive target for ovarian cancer therapy.

Keywords: Epithelial ovarian cancer, fibroblast growth factor receptor 2-IIIb, keratinocyte growth factor, ovarian surface epithelial


How to cite this article:
Wu J, Han W, Yang W, Liu H, Li C, Guo L, Jin Y, Zhang R, Chen H. Keratinocyte growth factor binding to fibroblast growth factor receptor 2-IIIb promotes epithelial ovarian cancer cell proliferation and invasion. J Can Res Ther 2018;14, Suppl S2:347-53

How to cite this URL:
Wu J, Han W, Yang W, Liu H, Li C, Guo L, Jin Y, Zhang R, Chen H. Keratinocyte growth factor binding to fibroblast growth factor receptor 2-IIIb promotes epithelial ovarian cancer cell proliferation and invasion. J Can Res Ther [serial online] 2018 [cited 2019 Sep 22];14:347-53. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/347/235353


 > Introduction Top


Keratinocyte growth factor (KGF), also known as fibroblast growth factor-7 (FGF-7), is predominantly released by mesenchymal original cells.[1] KGF acts through exclusively on fibroblast growth factors receptor 2 IIIb (FGFR2 IIIb).[2] There are two of splicing of FGFR2 gene FGFR2-IIIb and FGFR2-IIIc isoforms.[3] FGFR-2IIIc is mainly localized in mesenchymal cells, whereas FGFR2-IIIb is localized in epithelial cells.[4] Thus, we have examined the expression of KGF and its receptor GFR2IIIb in primary cultures of normal ovarian surface epithelial (OSE) and epithelial ovarian cancer (EOC) cell lines, and the EOC tissues obtained from patients undergoing surgery for EOC. KGF exerted its role through FGFR2-IIIb, which was found predominantly in epithelial cells but not in fibroblasts. We now report that FGFR2-IIIb expresses in EOCs cells and that KGF is usually present in normal OSE cells and tissues. Moreover, we demonstrate that EOC cell lines expressing FGFR2-IIIb can respond to KGF.

Extracellular signal-regulated kinase (ERK) is a member of MAPK signal transduction pathway. It has multiple functions in regulating cellular proliferation, differentiation, and metastasis of tumors.[5] ERK phosphorylates and activates myosin light chain kinase (MLCK), a known substrate for phospho-ERK. MLCK, in turn, phosphorylates and activates MLC.[6] Upon phosphorylation, MLC becomes active to promote cancer cell migration and invasion.[7] In this study, we demonstrate that KGF upregulates ERK and myosin light chain (MLC) phosphorylation in a highly invasive ovarian cancer cell line HO8910PM, which suggests that for the highly invasive ovarian cancer cells, KGF might promote proliferation and invasion through the ERK-MLC pathway.


 > Materials and Methods Top


Cell culture

Human ovarian cancer cell lines, HO8910PM and HO8910, were purchased from the Cell Bank of Shanghai Institutes for Biological Sciences, Chinese Academy of Science (Shanghai, China) and maintained at 37°C in a humidified incubator (Heraeus, Germany) containing 5% CO2, in Roswell Park Memorial Institute 1640 (RPMI-1640) medium, supplemented with 10% (v/v) heat-inactivated fetal bovine serum (FBS), 100 U/ml penicillin, and 100 μg/ml streptomycin. HO8910PM is a highly metastasizing human ovarian cancer cell line that is derived from HO8910.[8] Human OSE cells (HOSEpiCs) were purchased from the Shanghai Huiying Biological Technology Co., Ltd., (7310, Sciencell. China). HOSEpiC cells were grown in OEpiCM medium (7311, Sciencell) supplemented with 10% FBS, 1% penicillin, and 1% streptomycin in an atmosphere containing 5% CO2 and at a temperature of 37°C.

RPMI-1640 and FBS were obtained from Gibco BRL (Life Technologies, Paisley, Scotland). Bovine fibronectin and dimethyl sulfoxide were purchased from Sigma-Aldrich (St. Louis, MO, USA). All other reagents and solvents used in experiments were of analytical grade.

Tissue specimens

Tumor specimens are collected from a total of 71 ovarian tumor patients; seven normal ovarian tissues are collected from cervical cancer and cervical endometrial cancer resection of ovarian tissues. The 71 specimens of ovarian tumor tissues include serous cystadenoma (23 cases), ovarian borderline cystadenomas (13 cases), and high differentiation of epithelial ovarian cystadenocarcinoma (17 cases), low differentiated epithelial ovarian cystadenocarcinoma (report of 18 cases). All specimens are obtained from tumor hospital; grading and staging of the tumor are done by a gynecologic experienced pathologist in accordance with the FIGO and WHO diagnostic criteria. Patients' ages range from 29 to70 years; their median age is 49.5 years. All specimens are handled and made anonymous according to the ethical and legal standards.

Immunohistochemistry

The expression of KGF and FGFR2-IIIb protein in ovarian carcinoma tissues were analyzed by immunohistochemical SP staining. Immunohistochemical staining was conducted according to the manufacturer's protocol, and the sections were incubated with KGF (1:200, PeproTech, USA) and FGFR2-IIIb (1:200, B&D Systems, USA) biotinylated primary antibodies at 4°C overnight. Positive immunohistochemical staining is represented by brown stains visible under a light microscope.

Immunofluorescence assay

HOSEpiCs, HO8910, and HO8910PM cell lines were incubated with KGF antibody (1:200), FGFR2-IIIb antibody (1:200) 37°C for 1 h; FITC-conjugated secondary antibody (1:200) 37°C were incubated for 30 min. Fluorescence microscope (Olympus, Japan) were observed and photographed.

Western blot

Expression of keratinocyte growth factor in normal ovarian epithelial cells and epithelial ovarian cancer cell lines

HOSEpiCs, HO8910, and HO8910PM cells were cultured until subconfluence and were switched to serum-free medium for 24 h. After protein extraction, the samples were subjected to electrophoresis and then transferred to a Hybond ECL membrane. KGF antibody (1:500) was incubated at 37°C for 1 h. Then, the immunoblots were visualized with Western Blue (Promega, USA). β-actin expression was assessed as an internal loading control.

Keratinocyte growth factor-induced the ovarian cancer cell lines to express fibroblast growth factor receptor 2-IIIb

HO8910 and HO8910PM cells were cultured until subconfluence, then were switched to serum-free medium for 24 h. Cells were inoculated into 6-well plates; they were incubated with or without the KGF (100 pM) for 48 h. Then, these cells were lysed, and an equal amount of extracted proteins were analyzed by Western blot using anti-FGFR2-IIIb antibody (R&D Systems, USA 1:200) to detect FGFR2-IIIb protein expression. β-actin expression was assessed as an internal loading control.

Keratinocyte growth factor promotes the expression of phosphorylated extracellular signal-regulated kinase and myosin light chain

HO8910 and HO8910PM were cultured until subconfluence and then were switched to serum-free medium for 24 h. KGF protein was applied to the serum-starved HO8910 and HO8910PM for different lengths of time. The cells then were lysed and an equal amount of extracted proteins were analyzed by Western blot using anti-pMYL (1:200, Santa Cruz), anti-pERK (1:200, Santa Cruz), and anti-ERK (1:1000, Santa Cruz) to detect phosphorylated and total amounts of ERK1/2, MYL proteins, respectively.

Transwell invasion assay

To assess the effect of KGF on HO8910 and HO8910PM cells invasion ability after inhibit FGFR2-IIIb, the HO8910, and HO8910PM cells were added to the upper chamber and treated with FGFR2-IIIb primary antibody (1:500) for 2 h, followed by addition of KGF (100 pM). The cells then were incubated for 48 h to allow for invasion into the matrigel. Noninvading cells on the upper surface of the membrane were removed with a cotton swab. The invading cells on each membrane were counted in a microscope field at ×40 magnification.

Statistical analysis

The Student's t-test was used to analyze differences between the control and experimental groups. Differences were considered statically significant at *P < 0.05, **P < 0.01 (GraphPad Software, Inc., San Diego, CA, USA).


 > Results Top


Expression of keratinocyte growth factor

Immunofluorescence expression of KGF was observed in HOSEpiC cells and in normal OSE tissues but are not in HO8910 and HO8910PM cells [Figure 1]a. Western blot results corroborated the immunofluorescence assay [Figure 1]b. The immunohistochemistry assay showed KGF expression in OSE tissue, but not in the borders tumor, nor in well differentiated or poorly differentiated EOC tissues [Figure 1]c.
Figure 1: Immunofluorescence (a), Western blot (b), and immunohistochemistry (×200) (c). Keratinocyte growth factor expression in the normal ovarian epithelium, but expressed reduced distinctly in epithelial ovarian cancer cell line, and disappeared in high invasive ovarian cancer cell line (a and b). Immunohistochemistry assay show keratinocyte growth factor expression in ovarian surface epithelial tissue, but the borderline, well differentiations, and poor differentiation epithelial ovarian cancer tissue do not express keratinocyte growth factor (c)

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Expression of fibroblast growth factor receptor 2-IIIb in ovarian cancer cell lines or tissues

We studied the expression of FGFR2-IIIb by immunofluorescence [Figure 2]a and immunohistochemistry [Figure 2]b and [Figure 2]c. FGFR2-IIIb was not detected in HOSEpiC or NIH3T3 cells but was detected in HO8910 and HO8910PM cells. The ovarian cancer tissues expressing FGFR2-IIIb KGF are shown in [Table 1] and [Table 2]. FGFR2-IIIb expressed in OSE was much lower compared to that expressed in poorly differentiated cells (**P < 0.01).
Figure 2: (a) Immunofluorescence and immunohistochemistry assay expression fibroblast growth factor receptor 2 IIIb. Fibroblast growth factor receptor 2 IIIb antibody (1:200), fibroblast growth factor receptor 2 IIIb was not detected on HosEpiCs cells and NIH3T3 cells, but expression on HO8910 and HO8910PM cells. (b,c) Immunohistochemistry assay fibroblast growth factor receptor 2 IIIb expression on ovarian surface epithelial and epithelial ovarian cancers tissues. Fibroblast growth factor receptor 2 IIIb could not be detected on normal ovarian surface epithelial and ovarian borderline cystadenoma, but the expression on ovarian serous cystadenocarcinoma tissues increased significantly (*P < 0.05, **P < 0.01)

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Table 1: Expression of keratinocyte growth factor/fibroblast growth factor receptor 2-IIIb protein in different ovarian tissue

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Table 2: The relationship between the characteristics of epithelial ovarian tumor and clinical pathology

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Ovarian cancer cell lines expressed higher level of fibroblast growth factor receptor 2-IIIb responding to keratinocyte growth factor treatment

Western blot assay showed that FGFR2-IIIb protein expression in HO8910 and HO8910PM cells treated with KGF increased significantly comparing with that in nontreated cells [Figure 3]a. Transwells were used to measure cell invasiveness upon blocking of FGFR2-IIIb protein. The ovarian cancer cell lines responded to KGF stimulation, and the number of invasive cells increased significantly (**P < 0.01). After treatment with anti-FGFR2-IIIb antibody, the number of invasive cells decreased significantly (**P < 0.01) [Figure 3]b.
Figure 3: Fibroblast growth factor receptor 2-IIIb is an important signal transduction ligand of keratinocyte growth factor (a) Western blot assay shows that fibroblast growth factor receptor 2-IIIb protein expression of HO8910 and HO8910PM cells increased significantly after keratinocyte growth factor treatment (*P < 0.05,**P < 0.01), (b) transwells were used to measure cell invasiveness when fibroblast growth factor receptor 2-IIIb protein was blocked. The ovarian cancer cell lines responded to keratinocyte growth factor stimulation, the number of invasive cells increased significantly (**P < 0.01). After treated with anti-fibroblast growth factor receptor 2-IIIb antibody, the number of cells of invasive cells decreased significantly (**P < 0.01)

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The extracellular signal-regulated kinase-myosin light chain pathway is involved in invasional promotion of high invasive cell line HO8910PM by keratinocyte growth factor

HO8910 and HO8910PM cells were incubated in 100 pM KGF for 0.5 h, 1.5 h, 3 h, 6 h, 12 h, or 24 h. Western blot assays were used to detect ERK, p-ERK, MLC, and p-MLC expression. In HO8910PM cells, phosphorylation of ERK markedly increased after being treated with KGF for 0.5 h and 1 h; phosphorylation of MLC increased markedly after being treated with KGF for 6 h. However, in HO8910 cells, KGF did not promote p-ERK or p-MLC-protein expression (**P <0.01) [Figure 4].
Figure 4: (a) Western blot assay KGF promote MLC, p-MYL, ERK, p-ERK expression. HO8910, HO8910PM cells were treated with 100pM KGF for 0.5h, 1.5h, 3, 6h, 12h, 24h. Westernblotdetect ERK, p-ERK, MLC, p-MLC expression (**P <0.01). (b) For the HO8910PM cells phosphorylationof ERK was increased obviously after treatment with KGF at 0.5h and 1h, phosphorylatioof MLC was increased obviously aftertreatment with KGF for 6h. But for theHO8910 cells the KGF cannot promote p-ERK and p-MLC protein expression (**P <0.01)

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 > Discussion Top


Epithelial-mesenchymal cross talk has a very important role in the tumor microenvironment. Therefore, we investigated the expression of KGF, a crucial molecule for fibroblast in cancer invasion and proliferation. Our results support an important role for KGF in human EOC proliferation and invasion. In this study, we found that KGF stimulated the growth, migration, and invasion of ovary cancer cell lines HO8910 and HO8910PM by FGFR2-IIIb receptor. We showed that the expression of KGF's receptor FGFR2-IIIb increased in EOC cells and tissues comparing with its normal counterpart, and the expression of KGF protein decreased or undetectable in human EOC cells and tissues comparing with its normal part. The FGFR family binds to their ligands with high affinity.[9] Cho et al. found that KGFR and KGF were coexpressed in pancreatic cancer cell lines and that KGFR might be present at relatively high levels in these cells.[10],[11] Using FGFR multikinase inhibitor treatment pancreatic cancer cell line and patient-derived primary tumor explants achieved anti-cancer effect in pancreatic cancer correlated with the underlying FGFR signaling activity.[12] Their conclusions partially agree with our findings.

Although KGF produced by fibroblast, it promotes epithelial cells proliferation and invasion. Inflammatory factor interleukin-1 beta in stimulating fibroblast to production KGF is dose-related release.[13] In this study, we demonstrated that expression of the FGFR2-IIIb protein was induced in EOC cells and tissues by KGF protein. The expression of FGFR2-IIIb protein in the highly invasive ovarian cancer cell line HO8910PM was significantly higher than in the HO8910 cell line. Furthermore, FGFR2-IIIb protein expression dropped significantly when KGF stimulation was inhibition in the cancer cell lines. When the FGFR2-IIIb protein was inhibited by FGFR2-IIIb antibody, the ability of KGF protein to promote tumor cell invasion was significantly weakened. Thus, we conclude that KGF regulates ovarian cancer malignant progression and invasion by upregulating FGFR2-IIIb level. Recently, studies indicated that significant enhancement of cell proliferation and tumor progression in response to FGFR2 downregulation.[14]

The FGFR2-IIIb isoform has been reported to be restricted to epithelial cells.[15],[16],[17],[18] It is tempting to speculate that induction of the tumorigenic may be mediated, at least partially by FGFR2-IIIb.[19] These studies are consistent with our conclusions that KGF acts through the receptor FGFR2-IIIb expression on epithelial cells. The mechanisms of FGFR2-IIIb and KGF function in ovarian cancer cell differentiation, migration, and invasion remained unclear, therefore we further explored the molecular mechanisms involved in these processes and showed that the effects of KGF were mediated by the ERK and MLC pathways. ERK is a classic pathway for signal transduction. It possesses multiple functions in regulating cellular proliferation, differentiation, and apoptosis.[20] Our studies showed that in HO8910PM cells, phosphorylation of ERK markedly increased after being treated with KGF for 0.5 h and 1 h, and phosphorylation of MLC significantly increased after being treated with KGF for 6 h. However, in HO8910 cells, KGF could not promote the expression of p-ERK and p-MLC. It has been shown that phosphorylation of ERK substantially increased after being treated with KGF; KGF may exert its proliferation and invasion-promoting effects through the ERK pathway.[21] Activation of ERK also increased MLCK activity and MLC phosphorylation levels, strengthened actin-myosin contractile force, and promoted migration in extracellular matrix.[22] We speculate that KGF may act through the ERK-MLC pathway to promote highly invasive ovarian cancer cell proliferation and invasion. Studies have shown that activated ERK is critical for actin stress fiber formation through phosphorylation of MLC, which is required for the transition from quiescence to proliferation. MLC phosphorylation is a necessary condition for tumor cell proliferation because cell division depends on cytoskeletal activity. MLC phosphorylation alters the cytoskeleton cell-cell adhesion and cell-extracellular matrix adhesion, facilitating the migration of tumor cells.[23]


 > Conclusions Top


KGF, a protease secreted by fibroblasts, promoted HO8910 and HO8910PM cell invasion, migration and proliferation in this study. KGF, by signaling through its ligand, FGFR2-IIIb isoform, promotes ovarian cancer cell proliferation, migration, and invasion. For the highly invasive ovarian cancer cell line HO8910PM, the role of KGF may be mediated through the ERK-MLC pathway to promote ovarian cancer cell proliferation, migration, and invasion. KGF and its receptor FGFR2-IIIbisoform play key roles in ovarian cancer progression; they are attractive therapeutic targets for ovarian cancer.

Acknowledgments

The authors were supported in part by the Natural Science Foundation of Heilongjiang Province (No. D201049) by the Department of Science and Technology of Heilongjiang Province and the Opening Project of Key Laboratory of Medical Genetics, Harbin Medical University by Heilongjiang Higher Education Institutions, Harbin 150081, China.

Financial support and sponsorship

The authors were supported in part by the Natural Science Foundation of Heilongjiang Province (No. D201049) and supported by the Department of Science and Technology of Heilongjiang Province and the Opening Project of Key Laboratory of Medical Genetics, Harbin Medical University by Heilongjiang Higher Education Institutions, Harbin 150081, China.

Conflicts of interest

There are no conflicts of interest.

 
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