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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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API5 and pERK1/2 expression in human cervical neoplasias specimens. (A) Representative immunohistochemical staining images of API5 and pERK1/2 in normal, low grade CIN, high grade CIN, and cervical cancer tissues. Bars: 100 μm. (B) API5 IHC staining score in cervical neoplasia samples. API5 IHC staining score in cervical cancer samples was significantly higher than that of all other groups. The mean API5 score associated directly with each tumor stage, stage I tumors stained more weakly than stage II and stage IV tumors. API5 IHC staining score in poorly differentiated cervical cancer samples was significantly higher than that of well/moderately differentiated cancers.
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Fig3: API5 and pERK1/2 expression in human cervical neoplasias specimens. (A) Representative immunohistochemical staining images of API5 and pERK1/2 in normal, low grade CIN, high grade CIN, and cervical cancer tissues. Bars: 100 μm. (B) API5 IHC staining score in cervical neoplasia samples. API5 IHC staining score in cervical cancer samples was significantly higher than that of all other groups. The mean API5 score associated directly with each tumor stage, stage I tumors stained more weakly than stage II and stage IV tumors. API5 IHC staining score in poorly differentiated cervical cancer samples was significantly higher than that of well/moderately differentiated cancers.

Mentions: The TMA contains 173 cases of cervical cancer, however due to the complexity of sectioning, staining, as well as heterogeneity of the samples, only 152 and 150 samples could be interpreted for the API5 and pERK1/2, respectively. API5 protein expression was exclusively identified in the nucleus of tumor cells while the expression of pERK1/2 was detected in the cytoplasmic and nuclear of the tumor cells (Figure 3A). The expressions of API5 and pERK1/2 in relation to clinicopathologic characteristics were evaluated (Table 1). API5 expression gradually increased according to the phases of cervical cancer progression, from normal tissues through low and high grade CINs to cervical cancers (P < 0.001). Also, it correlated with features associated with advanced disease and poor outcome including FIGO stage (P = 0.004), tumor grade (P < 0.001), and chemo-radiation response (P = 0.004) (Figure 3B). In addition, subgroup analysis by stage was conducted for various stages of cervical cancer (Additional file 2: Table S2). The results were similar in all subgroups according to disease severity. The expression of pERK1/2 was up-regulated in high grade CIN and cancer specimens compared to normal and low grade CIN (P < 0.001, Table 1).Figure 3


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)

API5 and pERK1/2 expression in human cervical neoplasias specimens. (A) Representative immunohistochemical staining images of API5 and pERK1/2 in normal, low grade CIN, high grade CIN, and cervical cancer tissues. Bars: 100 μm. (B) API5 IHC staining score in cervical neoplasia samples. API5 IHC staining score in cervical cancer samples was significantly higher than that of all other groups. The mean API5 score associated directly with each tumor stage, stage I tumors stained more weakly than stage II and stage IV tumors. API5 IHC staining score in poorly differentiated cervical cancer samples was significantly higher than that of well/moderately differentiated cancers.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4125689&req=5

Fig3: API5 and pERK1/2 expression in human cervical neoplasias specimens. (A) Representative immunohistochemical staining images of API5 and pERK1/2 in normal, low grade CIN, high grade CIN, and cervical cancer tissues. Bars: 100 μm. (B) API5 IHC staining score in cervical neoplasia samples. API5 IHC staining score in cervical cancer samples was significantly higher than that of all other groups. The mean API5 score associated directly with each tumor stage, stage I tumors stained more weakly than stage II and stage IV tumors. API5 IHC staining score in poorly differentiated cervical cancer samples was significantly higher than that of well/moderately differentiated cancers.
Mentions: The TMA contains 173 cases of cervical cancer, however due to the complexity of sectioning, staining, as well as heterogeneity of the samples, only 152 and 150 samples could be interpreted for the API5 and pERK1/2, respectively. API5 protein expression was exclusively identified in the nucleus of tumor cells while the expression of pERK1/2 was detected in the cytoplasmic and nuclear of the tumor cells (Figure 3A). The expressions of API5 and pERK1/2 in relation to clinicopathologic characteristics were evaluated (Table 1). API5 expression gradually increased according to the phases of cervical cancer progression, from normal tissues through low and high grade CINs to cervical cancers (P < 0.001). Also, it correlated with features associated with advanced disease and poor outcome including FIGO stage (P = 0.004), tumor grade (P < 0.001), and chemo-radiation response (P = 0.004) (Figure 3B). In addition, subgroup analysis by stage was conducted for various stages of cervical cancer (Additional file 2: Table S2). The results were similar in all subgroups according to disease severity. The expression of pERK1/2 was up-regulated in high grade CIN and cancer specimens compared to normal and low grade CIN (P < 0.001, Table 1).Figure 3

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