Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and its heparan sulfate glycosaminoglycan side chains bind to several proteins exhibiting various biological roles. The authors have previously demonstrated syndecan-4′s critical roles in pulmonary inflammation. In the current study, however, its role in pulmonary fibrosis was evaluated. Wild-type and syndecan-4-deficient mice were injected with bleomycin, and several parameters of inflammation and fibrosis were analyzed. The mRNA expression of collagen and α-smooth muscle action (α-SMA) in lung tissues, as well as the histopathological lung fibrosis score and collagen content in lung tissues, were significantly higher in the syndecan-4-deficient mice. However, the total cell count and cell differentiation in bronchoalveolar lavage fluid were equivalent between the wild-type and syndecan-4-deficient mice. Although there was no difference in the TGF-β expression in lung tissues between the wild-type and syndecan-4-deficient mice, significantly more activation of Smad3 in lung tissues was observed in the syndecan-4-deficient mice compared to the wild-type mice. Furthermore, in the in vitro experiments using lung fibroblasts, the co-incubation of syndecan-4 significantly inhibited TGF-β-induced Smad3 activation, collagen and α-SMA upregulation. Moreover, syndecan-4 knock-down by siRNA increased TGF-β-induced Smad3 activation and upregulated collagen and α-SMA expression. These findings showed that syndecan-4 inhibits the development of pulmonary fibrosis, at least in part, through attenuating TGF-β signaling.

Alveolar epithelial damage is a critical event that leads to protein-rich edema in acute lung injury (ALI), but the mechanisms leading to epithelial damage are not completely understood. Cell death by necrosis and apoptosis occurs in alveolar epithelial cells in the lungs of patients with ALI. Fas activation induces apoptosis of alveolar epithelial cells, but its role in the formation of lung edema is unclear. The main goal of this study was to determine whether activation of the Fas/Fas ligand pathway in the lungs could alter the function of the lung epithelium, and the mechanisms involved. The results show that Fas activation alters the alveolar barrier integrity and impairs the ability of the lung alveolar epithelium to reabsorb fluid from the air spaces. This result was dependent on the presence of a normal Fas receptor and was not affected by inflammation induced by Fas activation. Alteration of the fluid transport properties of the alveolar epithelium was partially restored by β-adrenergic stimulation. Fas activation also caused apoptosis of alveolar endothelial cells, but this effect was less pronounced than the effect on the alveolar epithelium. Thus, activation of the Fas pathway impairs alveolar epithelial function in mouse lungs by mechanisms involving caspase-dependent apoptosis, suggesting that targeting apoptotic pathways could reduce the formation of lung edema in ALI.

Takahashi K, et al. J Gastric Cancer. 2021 Mar;21(1):103-109. https://doi.org/10.5230/jgc.2021.21.e11

Human telomerase reverse transcriptase (hTERT) is highly expressed in various cancers, including breast cancer. Although telomere elongation is an essential role for hTERT, the nuclear export after oxdative stress has also been shown in several cancer cell lines and is associated with drug-resistance in vitro. As only a few reports focused on the subcellular localization of hTERT in clinical specimens, we performed immunohistochemistry (IHC) and analyzed the correlation between intracellular hTERT expression and the clinicopathological characteristics to identify the clinical significance of hTERT sub -cellular expression in breast cancers. 144 invasive breast cancers classified by IHC subtype without primary systemic therapy (PST), were selected from a surgical resection cohort and were immunostained for hTERT, p-STAT3, p-AKT and p-ERK. The nuclear and/or cytoplasmic staining intensity and propor-tion of hTERT were scored and compared with clinicopathological parameters. The nuclear hTERT expression was significantly correlated with HER2 expression (p = 0.00156), and the scores were signif-icantly correlated with p-STAT3 and p-AKT expression scores (r = 0.532, p = 0.000587 and r = 0.345, p = 0.0339, respectively) in the HER2-immunopositive breast cancer including luminal-HER2 and HER2 subtypes. Furthermore, hTERT was expressed more in cytoplasm in the specimens after PST than those before PST, and the score tended to be negatively correlated with tumor shrinkage rate in HER2 sub-type (r = -0.593, p = 0.0705). These results suggest that nuclear and/or cytoplasmic hTERT may play a different role before and after PST including the tumorigenesis and drug-resistance in breast cancer. Sup-pression of cytoplasmic hTERT expression may lead to more effective strategy for drug-resistant HER2 subtype in breast cancer.(c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Lymphoepithelioma-like cholangiocarcinoma (LEL-CC) is a type of lymphoepithelioma-like carcinoma (LELC) and a rare variant of primary liver tumor. Although it is uncommon and only 100 cases have been reported thus far, the number of reports has increased in recent years. LEL-CC reportedly occurs more frequently in Asian women; Epstein–Barr virus (EBV) and hepatitis viruses are both strongly associated with tumor development. Here, we describe a 76-year-old woman who exhibited LEL-CC not associated with EBV or hepatitis virus. She was referred to our department with a 3.0-cm × 2.8-cm tumor in the left lobe of the liver. Based on computed tomography and magnetic resonance imaging findings, the tumor was preoperatively diagnosed as hepatocellular carcinoma. Thus, we performed extended left hepatectomy with caudal lobectomy. Histopathological examinations revealed columnar tumor cells with atypical nuclei that proliferated in a cord-like or glandular tubular pattern with dense lymphocytic infiltration. Immunohistochemical analysis showed negative HepPar-1 and arginase findings, indicating non-hepatocyte origin; however, the biliary-type cytokeratins CK7 and CK19 were detected. Based on these findings, the tumor was identified as LEL-CC. EBV-encoded RNA in situ hybridization findings were negative; the patient’s clinical characteristics were not suggestive of hepatitis virus infection. In conclusion, we suggest that clinicians consider LEL-CC as a differential diagnosis for liver tumors in Asian women, including patients without EBV or hepatitis virus.