Objectives

Abstract. Cholangiocarcinoma is frequently found to invade local tissues and metastasize to distal organs. We investigated the expression of CD24 in cholangiocarcinoma samples and its prognostic significance. In addition, the cellular function of CD24 was studied in the RMCCA1 cholangiocarcinoma cell line. High CD24 expression significantly correlated with lymph node metastasis and positive surgical margins in cholangiocarcinoma patients. Univariate and multivariate analyses further demonstrated that CD24 expression was significantly associated with the overall survival of these patients (p=0.007 and p=0.040, respectively). For in vitro studies, the magnetic-activated cell sorting (MACS) system was used to isolate CD24 + and CD24 -cell populations from RMCCA1 cells. CD24 + RMCCA1 cells had increased chemoresistance, adhesion (p=0.004), motility (p<0.001), migration (p<0.001) and invasion (p<0.001) capabilities when compared to CD24 -cells. The matrix metalloproteinase (MMP)-7 was significantly elevated in CD24 + RMCCA1 cells (p=0.01). We found that inhibition of CD24 using siRNA silencing significantly decreased the invasive capacity of RMCCA1 cells. Both clinical and in vitro studies suggest that expression of CD24 is associated with cholangiocarcinoma disease progression. CD24 may thus serve as a new target for directed molecular therapy of cholangiocarcinoma. IntroductionCholangiocarcinoma is one of the most aggressive malignant tumors associated with local tissue invasion and a high rate of metastasis and is one of the most common causes of cancer death in Thailand (1). Three-year survival rates of 35-50% are achieved only in a subset of patients who have negative histological margins at the time of surgery (2-5). Palliative therapeutic approaches, including percutaneous and endoscopic biliary drainage, have generally been used for these patients because there is no effective chemotherapeutic treatment for cholangiocarcinoma. Therefore, identification of the molecules involved in cholangiocarcinoma cell progression is crucial for the development of novel drug treatments for this disease.CD24 is a small, heavily glycosylated mucin-like glycosylphosphatidylinositol (GPI)-linked cell surface protein that serves as a ligand for P-selectin, an adhesion receptor on activated endothelial cells and platelets (6). CD24 can be detected in granulocytes, pre-B-cells and keratinocytes (7) and its expression in non-small cell lung cancer, ovarian cancer and hepatocellular carcinoma is associated with poor prognoses (8,9). However, only limited studies have been published on CD24 expression in cholangiocarcinoma (10,11) and there are no data on the mechanism of CD24 involvement in cholangiocarcinoma cell progression. In the present study, we investigated the clinicopathological significance of CD24 expression in human cholangiocarcinoma samples. We also determined the cellular function of CD24 in cholangiocarcinoma cells by isolating CD24 + and CD24 -cells from the RMCCA1 cholangiocarcinoma cell line and assessing cell pro...

Background: The programmed death-1/programmed death-ligand-1 (PD-1/PD-L1) axis may represent a target for cervical cancer; however, it is poorly understood in human immunodeficiency virus (HIV)-infected patients. Methods: We evaluated HIV-positive ( n = 42) and HIV-negative ( n = 110) women with locally advanced cervical cancer regarding their PD-L1 expression, determined by combined positive score (CPS) ⩾ 1 and tumor proportion score (TPS) ⩾ 25%, and PD-L1 copy number alterations, assessed by fluorescence in situ hybridization. Results: Regardless of HIV status, 84.9% and 44.8% of cases were PD-L1-positive according to CPS ⩾ 1 and TPS ⩾ 25%. Per CPS ⩾ 1, PD-L1 positive rate was similar between HIV-positive and HIV-negative women, whereas a significant difference was seen per TPS ⩾ 25%. Tumor size and parametrial invasion were correlated with PD-L1 positivity in HIV-negative women, whereas anti-retroviral therapy (ART) was correlated with TPS < 25%. Low CD4-positive cell counts were associated with CPS < 1 in HIV-positive women. No significant difference was observed in PD-L1 copy number status between HIV-positive and HIV-negative women. PD-L1 amplification and polysomy were independently associated with TPS ⩾ 25%, whereas the presence of parametrial invasion was independently associated with CPS ⩾ 1. Cancer stage and PD-L1 amplification were identified as independent predictors of recurrence-free survival [hazard ratio (HR) = 2.40 (1.32–4.36) and HR = 5.33 (1.94–14.61)] and cancer-specific survival [HR = 13.62 (5.1–36.38) and HR = 3.53 (1.43–8.69)]. PD-L1 polysomy was an independent predictor of locoregional recurrence-free survival [HR = 3.27 (1.27–8.41)]. HIV status and PD-L1 expression (CPS ⩾ 1 or TPS ⩾ 25%) were not associated with poor patient outcomes. Conclusion: PD-L1 amplification and polysomy are the strongest drivers of PD-L1 expression in cervical cancer, and could represent prognostic biomarkers for anti-PD-1/PD-L1 therapy. Cervical cancer biology may be modulated by HIV infection, CD4-positive cells, and HIV treatments.

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