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Pancreatic cancer ranks in the 10th–11th position among cancers affecting men in Taiwan, besides being a rather difficult-to-treat disease. The overall 5-year survival rate of pancreatic cancer is only 5–10%, while that of resectable pancreatic cancer is still approximately 15–20%. Cancer stem cells possess intrinsic detoxifying mechanisms that allow them to survive against conventional therapy by developing multidrug resistance. This study was conducted to investigate how to overcome chemoresistance and its mechanisms in pancreatic cancer stem cells (CSCs) using gemcitabine-resistant pancreatic cancer cell lines. Pancreatic CSCs were identified from human pancreatic cancer lines. To determine whether CSCs possess a chemoresistant phenotype, the sensitivity of unselected tumor cells, sorted CSCs, and tumor spheroid cells to fluorouracil (5-FU), gemcitabine (GEM), and cisplatin was analyzed under stem cell conditions or differentiating conditions. Although the mechanisms underlying multidrug resistance in CSCs are poorly understood, ABC transporters such as ABCG2, ABCB1, and ABCC1 are believed to be responsible. Therefore, we measured the mRNA expression levels of ABCG2, ABCB1, and ABCC1 by real-time RT-PCR. Our results showed that no significant differences were found in the effects of different concentrations of gemcitabine on CSCs CD44+/EpCAM+ of various PDAC cell line cultures (BxPC-3, Capan-1, and PANC-1). There was also no difference between CSCs and non-CSCs. Gemcitabine-resistant cells exhibited distinct morphological changes, including a spindle-shaped morphology, the appearance of pseudopodia, and reduced adhesion characteristics of transformed fibroblasts. These cells were found to be more invasive and migratory, and showed increased vimentin expression and decreased E-cadherin expression. Immunofluorescence and immunoblotting experiments demonstrated increased nuclear localization of total β-catenin. These alterations are hallmarks of epithelial-to-mesenchymal transition (EMT). Resistant cells showed activation of the receptor protein tyrosine kinase c-Met and increased expression of the stem cell marker cluster of differentiation (CD) 24, CD44, and epithelial specific antigen (ESA). We concluded that the expression of the ABCG2 transporter protein was significantly higher in CD44+ and EpCAM+ CSCs of PDAC cell lines. Cancer stem-like cells exhibited chemoresistance. Gemcitabine-resistant pancreatic tumor cells were associated with EMT, a more aggressive and invasive phenotype of numerous solid tumors. Increased phosphorylation of c-Met may also be related to chemoresistance, and EMT and could be used as an attractive adjunctive chemotherapeutic target in pancreatic cancer. [ABSTRACT FROM AUTHOR]

CD44 genetic variants have been found to be related to various cancers. However, to date, no study has demonstrated the involvement of CD44 polymorphisms in uterine cervical cancer in Taiwanese women. Therefore, we conducted a retrospective study, consecutively recruiting 113 patients with invasive cancer, 92 patients with high-grade cervical intraepithelial neoplasias, and 302 control women to assess the relationships among CD44 polymorphisms, cervical carcinogenesis, and patient survival. Real-time polymerase chain reaction was used to determine the genotypic distributions of six polymorphisms: rs1425802, rs187115, rs713330, rs11821102, rs10836347, and rs13347. The results revealed that women with the mutant homozygous genotype CC exhibited a higher risk of invasive cancer compared to those with the wild homozygous genotype TT [p=0.035; hazard ratio (HR)=10.29, 95% confidence interval (95% CI)=1.18-89.40] and TT/TC [p=0.032; HR=10.66, 95% CI=1.23-92.11] in the CD44 polymorphism rs713330. No significant association was found between CD44 genetic variants and clinicopathological parameters. Among the clinicopathological parameters, only positive pelvic lymph node metastasis (p=0.002; HR=8.57, 95% CI=2.14-34.38) and the AG/GG genotype compared to AA (p=0.014; HR=3.30, 95% CI=1.28-8.49) in CD44 polymorphism rs187115 predicted a higher risk of poor five-year survival, according to multivariate analysis. In conclusion, an important and novel finding revealed that Taiwanese women with the AG/GG genotype in CD44 polymorphism rs187115 exhibited a higher risk of poor five-year survival., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background and Objective CD44 is a transmembrane glycoprotein that exhibits various biological functions. Histological studies have shown that CD44 is expressed in periodontal ligament ( PDL). We investigated the role of CD44 in the in vitro biological functions of PDL cells. Material and Methods Immunohistochemistry and immunocytochemistry were used to examine CD44 protein expression in mouse molars and human PDL cells, respectively. PDL cells isolated from human third molars were assayed for their proliferation and mineralization after stably silencing their expression of CD44 using the small hairpin RNA technique. An osteogenesis-associated quantitative polymerase chain reaction array was used to identify downstream molecules of CD44 signaling in osteogenic medium. The PDL cells, transduced with control small hairpin RNA, were used as controls in all assays. Results PDLs expressed CD44 in vitro and in vivo. When CD44 expression was stably suppressed in PDL cells, their proliferation and mineralization activities in both media were substantially decreased. The quantitative polymerase chain reaction array and Western blotting verified that bone morphogenetic protein-2 (BMP-2), fibroblast growth factor-1 (FGF-1) and intercellular adhesion molecule-1 (ICAM-1) were downregulated after CD44 was knocked down in PDL cells. Exogenous FGF-1 attenuated the proliferative suppression of CD44 knockdown cells. Exogenous BMP-2 rescued the suppressed mineralization of CD44 knockdown cells more than ICAM-1 did. Conclusion The in vitro assays demonstrated that CD44 is crucial for the proliferation and mineralization of PDL cells and is possibly mediated by BMP-2, FGF-1 and ICAM-1. Further studies are required to verify the mediators and identify the physiological ligands of CD44 for possible application in periodontal regeneration. [ABSTRACT FROM AUTHOR]