Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma.

Epithelial ovarian cancer (EOC) is a leading cause of cancer-related mortality in the United States due to the late-stage disease at diagnosis. Overexpression of GRP78 and PDI following endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) promote growth and invasion in cancer. To identify novel prognostic biomarkers in EOC, here we determined the expression of ER stress-associated proteins (GRP78, ATF6 and PERK) and correlated with clinical outcome in EOC. Tissue microarray (TMA) samples from 415 tissues collected from three cancer centers (UM, USC, and KCCRI) were used to assess the expression levels of ER-associated proteins using immunohistochemistry (IHC). We observed that the expression levels of GRP78 (p < 0.0001), ATF6 (p < 0.0001), and PERK (p < 0.0001) were significantly increased in specimens of EOC compared to normal tissues, including in the serous subtype (p < 0.0001). Previously we reported that high expression of PDI correlated with poor patient survival in EOC. Here we showed that overexpression of GRP78 and PDI protein expression correlated with poor patient survival (p = 0.03), while low expression of combined GRP78 and PDI correlated with better survival (p = 0.01) in high-grade serous. The increased expression of ER stress-associated proteins in EOC suggests a role for ER stress and the UPR in EOC. More importantly, our results demonstrate that GRP78 and PDI are potential biomarkers for EOC and could be used as dual prognostic markers.

Using acetowhite opacity index for detecting cervical intraepithelial neoplasia.

Cervical intraepithelial neoplasia (CIN) exhibits certain morphologic features that can be identified during a colposcopic exam. Immature metaplastic and dysplastic cervical squamous epithelia turn white after application of acetic acid during the exam. The whitening process occurs visually over several minutes and subjectively helps to discriminate between dysplastic and normal tissue. Digital imaging technologies enable us to assist the physician in analyzing acetowhite (acetic-acid-induced) lesions in a fully automatic way. We report a study designed to measure multiple parameters of the acetowhitening process from two images captured with a digital colposcope. One image is captured before the acetic acid application, and the other is captured after the acetic acid application. The spatial change of the acetowhitening is extracted using color and texture information in the post-acetic-acid image; the temporal change is extracted from the intensity and color changes between the post-acetic-acid and pre-acetic-acid images with an automatic alignment. In particular, we propose an automatic means to calculate an opacity index that indicates the grades of temporal change. The imaging and data analysis system is evaluated with a total of 99 human subjects. The proposed opacity index demonstrates a sensitivity and specificity of 94 and 87%, respectively, for discriminating high-grade dysplasia (CIN2+) from normal and low-grade subjects, considering histology as the gold standard.

Expression of protein disulfide isomerase family members correlates with tumor progression and patient survival in ovarian cancer.

OBJECTIVE: Protein disulfide isomerase (PDI) is an oxidoreductase that is overexpressed in several cancers. PDI family members (PDIs) play a role in various diseases including cancer. Select PDIs were reported as useful markers in other cancers but their expression in ovarian cancer has not been thoroughly assessed. We sought to evaluate the expression of PDI, PDIA6, PDIR, ERp57, ERp72 and AGR3 in ovarian cancer patient samples and examine their prognostic significance. METHODS: TMA samples from 415 tissues collected from three cancer centers (UM, USC, and KCCRI) were used to assess the expression levels of PDI family proteins using IHC. RESULTS: We observed significant increases in PDI (p = 9.16E-36), PDIA6 (p = 5.51E-33), PDIR (p = 1.81E-12), ERp57 (p = 9.13E-07), ERp72 (p = 3.65E-22), and AGR3 (p = 4.56E-24) expression in ovarian cancers compared to normal tissues. Expression of PDI family members also increases during disease progression (p <0.001). All PDI family members are overexpressed in serous ovarian cancer (p<0.001). However, PDI, PDIA6, PDIR, ERp72 and AGR3 are more significantly overexpressed (p<0.001) than ERp57 (p<0.05) in clear cell ovarian carcinoma. Importantly, overexpression of PDI family members is associated with poor survival in ovarian cancer (p = 0.045 for PDI, p = 0.047 for PDIR, p = 0.037 for ERp57, p = 0.046 for ERp72, p = 0.040 for AGR3) with the exception of PDIA6 (p = 0.381). CONCLUSIONS: Our findings demonstrate that select PDI family members (PDI, PDIR, ERp72, ERp57 and AGR3) are potential prognostic markers for ovarian cancer.