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Prognostic significance of annexin A2 and annexin A4 expression in patients with cervical cancer.

Choi CH, Chung JY, Chung EJ, Sears JD, Lee JW, Bae DS, Hewitt SM - BMC Cancer (2016)

Bottom Line: ANXA2 overexpression was positively correlated with advanced cancer phenotypes, whereas ANXA4 expression was associated with resistance to radiation with or without chemotherapy (p = 0.029).Notably, high ANXA2 and ANXA4 expression was significantly associated with shorter disease-free survival (p = 0.004 and p = 0.033, respectively).Furthermore, a random survival forest model using combined ANXA2, ANXA4, and clinical variables resulted in improved predictive power (mean C-index, 0.76) compared to that of clinical-variable-only models (mean C-index, 0.70) (p = 0.006).

View Article: PubMed Central - PubMed

Affiliation: Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, MSC 1500, Bethesda, MD, 20892, USA.

ABSTRACT

Background: The annexins (ANXs) have diverse roles in tumor development and progression, however, their clinical significance in cervical cancer has not been elucidated. The present study was to investigate the clinical significance of annexin A2 (ANXA2) and annexin A4 (ANXA4) expression in cervical cancer.

Methods: ANXA2 and ANXA4 immunohistochemical staining were performed on a cervical cancer tissue microarray consisting of 46 normal cervical epithelium samples and 336 cervical cancer cases and compared the data with clinicopathological variables, including the survival of cervical cancer patients.

Results: ANXA2 expression was lower in cancer tissue (p = 0.002), whereas ANXA4 staining increased significantly in cancer tissues (p < 0.001). ANXA2 expression was more prominent in squamous cell carcinoma (p < 0.001), whereas ANXA4 was more highly expressed in adeno/adenosquamous carcinoma (p < 0.001). ANXA2 overexpression was positively correlated with advanced cancer phenotypes, whereas ANXA4 expression was associated with resistance to radiation with or without chemotherapy (p = 0.029). Notably, high ANXA2 and ANXA4 expression was significantly associated with shorter disease-free survival (p = 0.004 and p = 0.033, respectively). Multivariate analysis indicated that ANXA2+ (HR = 2.72, p = 0.003) and ANXA2+/ANXA4+ (HR = 2.69, p = 0.039) are independent prognostic factors of disease-free survival in cervical cancer. Furthermore, a random survival forest model using combined ANXA2, ANXA4, and clinical variables resulted in improved predictive power (mean C-index, 0.76) compared to that of clinical-variable-only models (mean C-index, 0.70) (p = 0.006).

Conclusions: These findings indicate that detecting ANXA2 and ANXA4 expression may aid the evaluation of cervical carcinoma prognosis.

No MeSH data available.


Related in: MedlinePlus

Representative immunohistochemical images of annexin A2 (ANXA2) and annexin A4 (ANXA4) in cervical cancer tissue. ANXA2 expression was strongly detected in the membranes of normal tissues (a), whereas ANXA4 staining was weakly observed in the cytoplasm of normal tissues (e). Negative staining demonstrated a lack of ANXA2 (b) and ANXA4 (f) expression. ANXA2 staining was mainly observed in the membranes of squamous cell carcinoma (c) and adenocarcinoma (d) cervical cancer tissues. ANXA4 staining was restricted to the cytoplasm of squamous cell carcinoma (g) and adenocarcinoma (h) (×200). Scale bar represents 50 μm
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Fig2: Representative immunohistochemical images of annexin A2 (ANXA2) and annexin A4 (ANXA4) in cervical cancer tissue. ANXA2 expression was strongly detected in the membranes of normal tissues (a), whereas ANXA4 staining was weakly observed in the cytoplasm of normal tissues (e). Negative staining demonstrated a lack of ANXA2 (b) and ANXA4 (f) expression. ANXA2 staining was mainly observed in the membranes of squamous cell carcinoma (c) and adenocarcinoma (d) cervical cancer tissues. ANXA4 staining was restricted to the cytoplasm of squamous cell carcinoma (g) and adenocarcinoma (h) (×200). Scale bar represents 50 μm

Mentions: Next, we performed Western blot using fractionated CaSki and HeLa cell lysates to examine the specificity anti-ANXA2 and anti-ANXA4 antibodies. ANXA4 was predominantly detected in the cytosolic fraction, whereas ANXA2 was detected in whole, cytosolic, and nuclear lysates (Fig. 1). The purities of the cytosolic and nuclear fractions were confirmed with calnexin and lamin B1, respectively. In addition, we performed immunohistochemistry in cervical cancer and normal tissues. ANXA2 staining was detected only in the membranes of normal cervical epithelium, whereas it was present in both the membranes and cytoplasm in cancerous tissues. ANXA4 staining was primarily observed in the cytoplasm. Representative examples of positive and negative staining are shown in Fig. 2. A significant increase in ANXA4 expression was detected in cancer tissues compared with that in normal cervix (mean histoscores; 73 vs. 34, p < 0.001). In contrast, ANXA2 expression was lower in cancer tissues than that in normal tissues (mean histoscores; 94 vs. 133, p = 0.002). A positive correlation was detected between mRNA and protein expression in patients with both protein and mRNA expression data from GSE44001 (Additional file 1: Figure S3).Fig. 1


Prognostic significance of annexin A2 and annexin A4 expression in patients with cervical cancer.

Choi CH, Chung JY, Chung EJ, Sears JD, Lee JW, Bae DS, Hewitt SM - BMC Cancer (2016)

Representative immunohistochemical images of annexin A2 (ANXA2) and annexin A4 (ANXA4) in cervical cancer tissue. ANXA2 expression was strongly detected in the membranes of normal tissues (a), whereas ANXA4 staining was weakly observed in the cytoplasm of normal tissues (e). Negative staining demonstrated a lack of ANXA2 (b) and ANXA4 (f) expression. ANXA2 staining was mainly observed in the membranes of squamous cell carcinoma (c) and adenocarcinoma (d) cervical cancer tissues. ANXA4 staining was restricted to the cytoplasm of squamous cell carcinoma (g) and adenocarcinoma (h) (×200). Scale bar represents 50 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940752&req=5

Fig2: Representative immunohistochemical images of annexin A2 (ANXA2) and annexin A4 (ANXA4) in cervical cancer tissue. ANXA2 expression was strongly detected in the membranes of normal tissues (a), whereas ANXA4 staining was weakly observed in the cytoplasm of normal tissues (e). Negative staining demonstrated a lack of ANXA2 (b) and ANXA4 (f) expression. ANXA2 staining was mainly observed in the membranes of squamous cell carcinoma (c) and adenocarcinoma (d) cervical cancer tissues. ANXA4 staining was restricted to the cytoplasm of squamous cell carcinoma (g) and adenocarcinoma (h) (×200). Scale bar represents 50 μm
Mentions: Next, we performed Western blot using fractionated CaSki and HeLa cell lysates to examine the specificity anti-ANXA2 and anti-ANXA4 antibodies. ANXA4 was predominantly detected in the cytosolic fraction, whereas ANXA2 was detected in whole, cytosolic, and nuclear lysates (Fig. 1). The purities of the cytosolic and nuclear fractions were confirmed with calnexin and lamin B1, respectively. In addition, we performed immunohistochemistry in cervical cancer and normal tissues. ANXA2 staining was detected only in the membranes of normal cervical epithelium, whereas it was present in both the membranes and cytoplasm in cancerous tissues. ANXA4 staining was primarily observed in the cytoplasm. Representative examples of positive and negative staining are shown in Fig. 2. A significant increase in ANXA4 expression was detected in cancer tissues compared with that in normal cervix (mean histoscores; 73 vs. 34, p < 0.001). In contrast, ANXA2 expression was lower in cancer tissues than that in normal tissues (mean histoscores; 94 vs. 133, p = 0.002). A positive correlation was detected between mRNA and protein expression in patients with both protein and mRNA expression data from GSE44001 (Additional file 1: Figure S3).Fig. 1

Bottom Line: ANXA2 overexpression was positively correlated with advanced cancer phenotypes, whereas ANXA4 expression was associated with resistance to radiation with or without chemotherapy (p = 0.029).Notably, high ANXA2 and ANXA4 expression was significantly associated with shorter disease-free survival (p = 0.004 and p = 0.033, respectively).Furthermore, a random survival forest model using combined ANXA2, ANXA4, and clinical variables resulted in improved predictive power (mean C-index, 0.76) compared to that of clinical-variable-only models (mean C-index, 0.70) (p = 0.006).

View Article: PubMed Central - PubMed

Affiliation: Experimental Pathology Laboratory, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, MSC 1500, Bethesda, MD, 20892, USA.

ABSTRACT

Background: The annexins (ANXs) have diverse roles in tumor development and progression, however, their clinical significance in cervical cancer has not been elucidated. The present study was to investigate the clinical significance of annexin A2 (ANXA2) and annexin A4 (ANXA4) expression in cervical cancer.

Methods: ANXA2 and ANXA4 immunohistochemical staining were performed on a cervical cancer tissue microarray consisting of 46 normal cervical epithelium samples and 336 cervical cancer cases and compared the data with clinicopathological variables, including the survival of cervical cancer patients.

Results: ANXA2 expression was lower in cancer tissue (p = 0.002), whereas ANXA4 staining increased significantly in cancer tissues (p < 0.001). ANXA2 expression was more prominent in squamous cell carcinoma (p < 0.001), whereas ANXA4 was more highly expressed in adeno/adenosquamous carcinoma (p < 0.001). ANXA2 overexpression was positively correlated with advanced cancer phenotypes, whereas ANXA4 expression was associated with resistance to radiation with or without chemotherapy (p = 0.029). Notably, high ANXA2 and ANXA4 expression was significantly associated with shorter disease-free survival (p = 0.004 and p = 0.033, respectively). Multivariate analysis indicated that ANXA2+ (HR = 2.72, p = 0.003) and ANXA2+/ANXA4+ (HR = 2.69, p = 0.039) are independent prognostic factors of disease-free survival in cervical cancer. Furthermore, a random survival forest model using combined ANXA2, ANXA4, and clinical variables resulted in improved predictive power (mean C-index, 0.76) compared to that of clinical-variable-only models (mean C-index, 0.70) (p = 0.006).

Conclusions: These findings indicate that detecting ANXA2 and ANXA4 expression may aid the evaluation of cervical carcinoma prognosis.

No MeSH data available.


Related in: MedlinePlus