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Apoptosis inhibitor-5 overexpression is associated with tumor progression and poor prognosis in patients with cervical cancer.

Cho H, Chung JY, Song KH, Noh KH, Kim BW, Chung EJ, Ylaya K, Kim JH, Kim TW, Hewitt SM, Kim JH - BMC Cancer (2014)

Bottom Line: Immunohistochemical staining showed that API5 expression increased during the normal to tumor transition of cervical carcinoma (P < 0.001), and this increased expression was significantly associated with tumor stage (P = 0.004), tumor grade (P < 0.001), and chemo-radiation response (P = 0.004).In multivariate analysis, API5+ (P = 0.039) and combined API5+/pERK1/2+ (P = 0.032) were independent prognostic factors for overall survival.API5 expression is associated with pERK1/2 in a subset of cervical cancer patients and its expression predicts poor overall survival, supporting that API5 may be a promising novel target for therapeutic interventions.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, 146-92 Dogok-Dong, Gangnam-Gu, Seoul 135-720, South Korea. genejock@helix.nih.gov.

ABSTRACT

Background: The apoptosis inhibitor-5 (API5), anti-apoptosis protein, is considered a key molecule in the tumor progression and malignant phenotype of tumor cells. Here, we investigated API5 expression in cervical cancer, its clinical significance, and its relationship with phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) in development and progression of cervical cancer.

Methods: API5 effects on cell growth were assessed in cervical cancer cell lines. API5 and pERK1/2 immunohistochemical staining were performed on a cervical cancer tissue microarray consisting of 173 primary cervical cancers, 306 cervical intraepithelial neoplasias (CINs), and 429 matched normal tissues.

Results: API5 overexpression promoted cell proliferation and colony formation in CaSki cells, whereas API5 knockdown inhibited the both properties in HeLa cells. Immunohistochemical staining showed that API5 expression increased during the normal to tumor transition of cervical carcinoma (P < 0.001), and this increased expression was significantly associated with tumor stage (P = 0.004), tumor grade (P < 0.001), and chemo-radiation response (P = 0.004). API5 expression levels were positively associated with pERK1/2 in cervical cancer (P < 0.001) and high grade CIN (P = 0.031). In multivariate analysis, API5+ (P = 0.039) and combined API5+/pERK1/2+ (P = 0.032) were independent prognostic factors for overall survival.

Conclusions: API5 expression is associated with pERK1/2 in a subset of cervical cancer patients and its expression predicts poor overall survival, supporting that API5 may be a promising novel target for therapeutic interventions.

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Related in: MedlinePlus

Kaplan–Meier plots of disease-free survival (A - C) and overall survival (D - F) categorized based on API5 expression, pERK1/2 expression, and co-expression of API5/pERK1/2. High API5 expression associated with short disease-free survival (A, P = 0.001) and overall survival rate (D, P = 0.001). Patients with high pERK1/2 expression displayed worse overall survival (E, P = 0.040). The association of high API5/pERK1/2 with disease-free survival (C) and overall survival (F) was significantly different from that of low API5/pERK1/2 (P < 0.001 for both).
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Fig4: Kaplan–Meier plots of disease-free survival (A - C) and overall survival (D - F) categorized based on API5 expression, pERK1/2 expression, and co-expression of API5/pERK1/2. High API5 expression associated with short disease-free survival (A, P = 0.001) and overall survival rate (D, P = 0.001). Patients with high pERK1/2 expression displayed worse overall survival (E, P = 0.040). The association of high API5/pERK1/2 with disease-free survival (C) and overall survival (F) was significantly different from that of low API5/pERK1/2 (P < 0.001 for both).

Mentions: We next examined the relationship of API5 expression to patient outcome. As shown in Figure 4, Kaplan-Meier plots demonstrated that patients with high API5 expression (IHC score of ≥ 8) displayed significantly shorter disease-free survival (mean of 41.5 versus 53.0 months, P = 0.001) and overall survival (mean of 48.8 versus 58.4 months, P < 0.001) (Figure 4A and C). The high pERK1/2 expression (IHC score of ≥ 4) group had shorter survival whereas the low pERK1/2 expression group had longer survival in overall survival analysis (mean of 52.3 versus 56.7 months, P = 0.040) (Figure 4E). Furthermore, the patients with combined high API5 and high pERK1/2 expression showed significantly shorter disease-free survival (mean of 33.2 versus 52.2 months, P < 0.001) and overall survival (mean of 44.4 versus 58.6 months, P < 0.001) than patients who were low API5 and low pERK1/2 expression (Figure 4C and F). The independent prognostic significance of high API5 expression and a combined high API5 and high pERK1/2 expression as well as other clinicopathologic parameters was determined by applying Cox proportional hazards model. FIGO stage (P = 0.001), LN metastasis (P = 0.047), high API5 expression (P = 0.031), and a combination of high API5 and high pERK1/2 expression (P = 0.007) were related to shorter disease-free survival (Table 3). Furthermore, SCC cell type [hazard ratio = 0.23 (95% CI, 0.06-0.80), P = 0.021], LN metastasis [hazard ratio = 3.85 (95% CI, 1.08-13.73), P = 0.038], high API5 expression [hazard ratio = 3.98 (95% CI, 1.07-14.85), P = 0.039], and a combination of high API5 and high pERK1/2 expression [hazard ratio = 4.14 (95% CI, 1.12-15.21), P = 0.032] were the independent prognostic factors with respect to overall survival. Altogether, these data indicated that API5 expression serves as an important prognostic factor in human cervical cancer.Figure 4


Apoptosis inhibitor-5 overexpression is associated with tumor progression and poor prognosis in patients with cervical cancer.

Cho H, Chung JY, Song KH, Noh KH, Kim BW, Chung EJ, Ylaya K, Kim JH, Kim TW, Hewitt SM, Kim JH - BMC Cancer (2014)

Kaplan–Meier plots of disease-free survival (A - C) and overall survival (D - F) categorized based on API5 expression, pERK1/2 expression, and co-expression of API5/pERK1/2. High API5 expression associated with short disease-free survival (A, P = 0.001) and overall survival rate (D, P = 0.001). Patients with high pERK1/2 expression displayed worse overall survival (E, P = 0.040). The association of high API5/pERK1/2 with disease-free survival (C) and overall survival (F) was significantly different from that of low API5/pERK1/2 (P < 0.001 for both).
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Fig4: Kaplan–Meier plots of disease-free survival (A - C) and overall survival (D - F) categorized based on API5 expression, pERK1/2 expression, and co-expression of API5/pERK1/2. High API5 expression associated with short disease-free survival (A, P = 0.001) and overall survival rate (D, P = 0.001). Patients with high pERK1/2 expression displayed worse overall survival (E, P = 0.040). The association of high API5/pERK1/2 with disease-free survival (C) and overall survival (F) was significantly different from that of low API5/pERK1/2 (P < 0.001 for both).
Mentions: We next examined the relationship of API5 expression to patient outcome. As shown in Figure 4, Kaplan-Meier plots demonstrated that patients with high API5 expression (IHC score of ≥ 8) displayed significantly shorter disease-free survival (mean of 41.5 versus 53.0 months, P = 0.001) and overall survival (mean of 48.8 versus 58.4 months, P < 0.001) (Figure 4A and C). The high pERK1/2 expression (IHC score of ≥ 4) group had shorter survival whereas the low pERK1/2 expression group had longer survival in overall survival analysis (mean of 52.3 versus 56.7 months, P = 0.040) (Figure 4E). Furthermore, the patients with combined high API5 and high pERK1/2 expression showed significantly shorter disease-free survival (mean of 33.2 versus 52.2 months, P < 0.001) and overall survival (mean of 44.4 versus 58.6 months, P < 0.001) than patients who were low API5 and low pERK1/2 expression (Figure 4C and F). The independent prognostic significance of high API5 expression and a combined high API5 and high pERK1/2 expression as well as other clinicopathologic parameters was determined by applying Cox proportional hazards model. FIGO stage (P = 0.001), LN metastasis (P = 0.047), high API5 expression (P = 0.031), and a combination of high API5 and high pERK1/2 expression (P = 0.007) were related to shorter disease-free survival (Table 3). Furthermore, SCC cell type [hazard ratio = 0.23 (95% CI, 0.06-0.80), P = 0.021], LN metastasis [hazard ratio = 3.85 (95% CI, 1.08-13.73), P = 0.038], high API5 expression [hazard ratio = 3.98 (95% CI, 1.07-14.85), P = 0.039], and a combination of high API5 and high pERK1/2 expression [hazard ratio = 4.14 (95% CI, 1.12-15.21), P = 0.032] were the independent prognostic factors with respect to overall survival. Altogether, these data indicated that API5 expression serves as an important prognostic factor in human cervical cancer.Figure 4

Bottom Line: Immunohistochemical staining showed that API5 expression increased during the normal to tumor transition of cervical carcinoma (P < 0.001), and this increased expression was significantly associated with tumor stage (P = 0.004), tumor grade (P < 0.001), and chemo-radiation response (P = 0.004).In multivariate analysis, API5+ (P = 0.039) and combined API5+/pERK1/2+ (P = 0.032) were independent prognostic factors for overall survival.API5 expression is associated with pERK1/2 in a subset of cervical cancer patients and its expression predicts poor overall survival, supporting that API5 may be a promising novel target for therapeutic interventions.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, 146-92 Dogok-Dong, Gangnam-Gu, Seoul 135-720, South Korea. genejock@helix.nih.gov.

ABSTRACT

Background: The apoptosis inhibitor-5 (API5), anti-apoptosis protein, is considered a key molecule in the tumor progression and malignant phenotype of tumor cells. Here, we investigated API5 expression in cervical cancer, its clinical significance, and its relationship with phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) in development and progression of cervical cancer.

Methods: API5 effects on cell growth were assessed in cervical cancer cell lines. API5 and pERK1/2 immunohistochemical staining were performed on a cervical cancer tissue microarray consisting of 173 primary cervical cancers, 306 cervical intraepithelial neoplasias (CINs), and 429 matched normal tissues.

Results: API5 overexpression promoted cell proliferation and colony formation in CaSki cells, whereas API5 knockdown inhibited the both properties in HeLa cells. Immunohistochemical staining showed that API5 expression increased during the normal to tumor transition of cervical carcinoma (P < 0.001), and this increased expression was significantly associated with tumor stage (P = 0.004), tumor grade (P < 0.001), and chemo-radiation response (P = 0.004). API5 expression levels were positively associated with pERK1/2 in cervical cancer (P < 0.001) and high grade CIN (P = 0.031). In multivariate analysis, API5+ (P = 0.039) and combined API5+/pERK1/2+ (P = 0.032) were independent prognostic factors for overall survival.

Conclusions: API5 expression is associated with pERK1/2 in a subset of cervical cancer patients and its expression predicts poor overall survival, supporting that API5 may be a promising novel target for therapeutic interventions.

Show MeSH
Related in: MedlinePlus