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Fibulin-4 is associated with tumor progression and a poor prognosis in ovarian carcinomas.

Chen J, Liu Z, Fang S, Fang R, Liu X, Zhao Y, Li X, Huang L, Zhang J - BMC Cancer (2015)

Bottom Line: Fibulin-4 expression was upregulated in ovarian carcinoma, and positively correlated with MVD and VEGF expression.The serum levels of fibulin-4, CA-125 and CA19-9 in patients with ovarian carcinoma were much higher than those with benign ovarian tumors and normal controls.Compared to CA-125 and CA19-9, fibulin-4 had better diagnostic sensitivity and specificity.

View Article: PubMed Central - PubMed

Affiliation: Department of Maternal and Child Health Care, School of Public Health, Shandong University, Jinan, 250012, China. 77chenjie@sdu.edu.cn.

ABSTRACT

Background: Fibulin-4, a member of the fibulin family of extracellular glycoproteins, is implicated in the progressions of some cancers. However, no information has been available to date regarding the function of fibulin-4 in ovarian carcinoma progression.

Methods: In this study, fibulin-4 mRNA and protein expression in normal ovarian tissue, ovarian tumor, high invasive subclones and low invasive subclones were evaluated by immunohistochemistry and real time reverse transcriptase-polymerase chain reaction (RT-PCR). The serum levels of fibulin-4, cancer antigen 125 (CA-125) and cerbohydrate antigen 199 (CA19-9) in patients with ovarian tumor were measured by enzyme-linked immunosorbent assay and electrochemiluminescent immunoassay. To assess the angiogenic properties of fibulin-4, vascular endothelial growth factor (VEGF) expression and tumor microvessel density were analyzed in ovarian carcinoma by immunohistochemistry.

Results: Fibulin-4 expression was upregulated in ovarian carcinoma, and positively correlated with MVD and VEGF expression. Fibulin-4 overexpression was significantly associated with advanced stage, low differentiation, lymph node metastasis and poor prognosis in patients with ovarian cancer. The serum levels of fibulin-4, CA-125 and CA19-9 in patients with ovarian carcinoma were much higher than those with benign ovarian tumors and normal controls. Compared to CA-125 and CA19-9, fibulin-4 had better diagnostic sensitivity and specificity.

Conclusions: Fibulin-4 is a novel gene that is found overexpressed in ovarian cancer and associated with poor prognostic clinicopathologic features. This study shows that fibulin-4 may serve as a new prognostic factor and as a potential therapeutic target for patients with ovarian cancer in the future.

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Kaplan-Meier analysis and VEGF expressions in highly invasive subclones and low invasive subclones.(A) 160 patients with invasive cancer were included in the cohort. Patients with high EFEMP1 expression (green line, n = 115) had a much worse prognosis than those with low EFEMP1 expression (blue line, n = 45). (B) Fibulin-4 mRNA expressions of highly invasive subclones S1 and A1 and low invasive subclones S21 and A19 as measured by q-RT-PCR. (C) Fibulin-4 protein expressions of highly invasive subclones and low invasive subclones as measured by ICC staining (Magnification × 200). (D) Fibulin-4 protein expressions of highly invasive subclones and low invasive subclones as measured by Western blot. *P < 0.05 versus control.
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Fig2: Kaplan-Meier analysis and VEGF expressions in highly invasive subclones and low invasive subclones.(A) 160 patients with invasive cancer were included in the cohort. Patients with high EFEMP1 expression (green line, n = 115) had a much worse prognosis than those with low EFEMP1 expression (blue line, n = 45). (B) Fibulin-4 mRNA expressions of highly invasive subclones S1 and A1 and low invasive subclones S21 and A19 as measured by q-RT-PCR. (C) Fibulin-4 protein expressions of highly invasive subclones and low invasive subclones as measured by ICC staining (Magnification × 200). (D) Fibulin-4 protein expressions of highly invasive subclones and low invasive subclones as measured by Western blot. *P < 0.05 versus control.

Mentions: As shown in Figure 1, in normal human ovarian surface epithelial cells, fibulin-4 protein expression was very low (Figure 1A), and in the ovarian stroma, fibulin-4 protein expression was mainly focused around the vasculatures (Figure 1B). However in most ovarian carcinomas, fibulin-4 immunoreactivity was high, and high fibulin-4 protein expression was found in the cytoplasm of ovarian cancer cells (Figure 1E,F,G). Moreover, high fibulin-4 protein expression was associated with low differentiation, advanced stage and positive lymph node status of ovarian carcinomas (Table 1). The interobserver reliability coefficients were 0.84 and 0.87 for the first and second assessments, with an intraobserver reproducibility coefficient of 0.86. The interobserver reliability and intraobserver reproducibility of IHC experiments were excellent. Similar results were also shown in the real time RT-PCR experiment, fibulin-4 mRNA expression was also very low in normal ovarian tissues and benign ovarian tumors, and significantly high fibulin-4 expression was seen in ovarian carcinoma. Moreover, high fibulin-4 mRNA expression was also associated with low differentiation, advanced stage and positive lymph node status of ovarian carcinomas (Table 2). To evaluate the prognostic value of fibulin-4 in ovarian cancer, we performed survival analysis using Kaplan-Meier analysis. The result showed that patients with high fibulin-4 expression had a much worse prognosis than those with low fibulin-4 expression (log rank, P < 0.01; Figure 2A). In multivariate analysis, considering all histological and molecular features together, the important prognostic factors were fibulin-4 expression (P = 0.000; hazard ratio 2.129), lymph node metastasis (P = 0.001; hazard ratio 1.017), and tumor stage (P = 0.005; hazard ratio 1.984) (Table 3).Figure 1


Fibulin-4 is associated with tumor progression and a poor prognosis in ovarian carcinomas.

Chen J, Liu Z, Fang S, Fang R, Liu X, Zhao Y, Li X, Huang L, Zhang J - BMC Cancer (2015)

Kaplan-Meier analysis and VEGF expressions in highly invasive subclones and low invasive subclones.(A) 160 patients with invasive cancer were included in the cohort. Patients with high EFEMP1 expression (green line, n = 115) had a much worse prognosis than those with low EFEMP1 expression (blue line, n = 45). (B) Fibulin-4 mRNA expressions of highly invasive subclones S1 and A1 and low invasive subclones S21 and A19 as measured by q-RT-PCR. (C) Fibulin-4 protein expressions of highly invasive subclones and low invasive subclones as measured by ICC staining (Magnification × 200). (D) Fibulin-4 protein expressions of highly invasive subclones and low invasive subclones as measured by Western blot. *P < 0.05 versus control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359517&req=5

Fig2: Kaplan-Meier analysis and VEGF expressions in highly invasive subclones and low invasive subclones.(A) 160 patients with invasive cancer were included in the cohort. Patients with high EFEMP1 expression (green line, n = 115) had a much worse prognosis than those with low EFEMP1 expression (blue line, n = 45). (B) Fibulin-4 mRNA expressions of highly invasive subclones S1 and A1 and low invasive subclones S21 and A19 as measured by q-RT-PCR. (C) Fibulin-4 protein expressions of highly invasive subclones and low invasive subclones as measured by ICC staining (Magnification × 200). (D) Fibulin-4 protein expressions of highly invasive subclones and low invasive subclones as measured by Western blot. *P < 0.05 versus control.
Mentions: As shown in Figure 1, in normal human ovarian surface epithelial cells, fibulin-4 protein expression was very low (Figure 1A), and in the ovarian stroma, fibulin-4 protein expression was mainly focused around the vasculatures (Figure 1B). However in most ovarian carcinomas, fibulin-4 immunoreactivity was high, and high fibulin-4 protein expression was found in the cytoplasm of ovarian cancer cells (Figure 1E,F,G). Moreover, high fibulin-4 protein expression was associated with low differentiation, advanced stage and positive lymph node status of ovarian carcinomas (Table 1). The interobserver reliability coefficients were 0.84 and 0.87 for the first and second assessments, with an intraobserver reproducibility coefficient of 0.86. The interobserver reliability and intraobserver reproducibility of IHC experiments were excellent. Similar results were also shown in the real time RT-PCR experiment, fibulin-4 mRNA expression was also very low in normal ovarian tissues and benign ovarian tumors, and significantly high fibulin-4 expression was seen in ovarian carcinoma. Moreover, high fibulin-4 mRNA expression was also associated with low differentiation, advanced stage and positive lymph node status of ovarian carcinomas (Table 2). To evaluate the prognostic value of fibulin-4 in ovarian cancer, we performed survival analysis using Kaplan-Meier analysis. The result showed that patients with high fibulin-4 expression had a much worse prognosis than those with low fibulin-4 expression (log rank, P < 0.01; Figure 2A). In multivariate analysis, considering all histological and molecular features together, the important prognostic factors were fibulin-4 expression (P = 0.000; hazard ratio 2.129), lymph node metastasis (P = 0.001; hazard ratio 1.017), and tumor stage (P = 0.005; hazard ratio 1.984) (Table 3).Figure 1

Bottom Line: Fibulin-4 expression was upregulated in ovarian carcinoma, and positively correlated with MVD and VEGF expression.The serum levels of fibulin-4, CA-125 and CA19-9 in patients with ovarian carcinoma were much higher than those with benign ovarian tumors and normal controls.Compared to CA-125 and CA19-9, fibulin-4 had better diagnostic sensitivity and specificity.

View Article: PubMed Central - PubMed

Affiliation: Department of Maternal and Child Health Care, School of Public Health, Shandong University, Jinan, 250012, China. 77chenjie@sdu.edu.cn.

ABSTRACT

Background: Fibulin-4, a member of the fibulin family of extracellular glycoproteins, is implicated in the progressions of some cancers. However, no information has been available to date regarding the function of fibulin-4 in ovarian carcinoma progression.

Methods: In this study, fibulin-4 mRNA and protein expression in normal ovarian tissue, ovarian tumor, high invasive subclones and low invasive subclones were evaluated by immunohistochemistry and real time reverse transcriptase-polymerase chain reaction (RT-PCR). The serum levels of fibulin-4, cancer antigen 125 (CA-125) and cerbohydrate antigen 199 (CA19-9) in patients with ovarian tumor were measured by enzyme-linked immunosorbent assay and electrochemiluminescent immunoassay. To assess the angiogenic properties of fibulin-4, vascular endothelial growth factor (VEGF) expression and tumor microvessel density were analyzed in ovarian carcinoma by immunohistochemistry.

Results: Fibulin-4 expression was upregulated in ovarian carcinoma, and positively correlated with MVD and VEGF expression. Fibulin-4 overexpression was significantly associated with advanced stage, low differentiation, lymph node metastasis and poor prognosis in patients with ovarian cancer. The serum levels of fibulin-4, CA-125 and CA19-9 in patients with ovarian carcinoma were much higher than those with benign ovarian tumors and normal controls. Compared to CA-125 and CA19-9, fibulin-4 had better diagnostic sensitivity and specificity.

Conclusions: Fibulin-4 is a novel gene that is found overexpressed in ovarian cancer and associated with poor prognostic clinicopathologic features. This study shows that fibulin-4 may serve as a new prognostic factor and as a potential therapeutic target for patients with ovarian cancer in the future.

Show MeSH
Related in: MedlinePlus