Prognostic Significance of S100A4 in Ovarian Clear Cell Carcinoma: Its Relation to Tumor Progression and Chemoresistance

Background/Objectives: S100A4, a small calcium-binding protein, promotes metastasis in a variety of human malignancies, but little is known about its involvement in ovarian clear cell carcinoma (OCCC). Herein, we characterized the functional role of S100A4 in this tumor type. Methods: We analyzed immunohistochemical sections from 120 OCCC patients. OCCC cell lines in which S100A4 was knocked out (KO) or overexpressed were also used to study the protein’s effects. Results: Stable overexpression of S100A4 decreased the proliferation of OCCC cell lines (concomitant with more cells in G1 and fewer in the G2/M phase of the cell cycle). S100A4 overexpression also reduced susceptibility to cisplatin-induced apoptosis (probably due to an increased BCL2: BAX ratio), accelerated epithelial–mesenchymal transition (EMT)-related cell mobility, and enhanced cancer stem cell (CSC) properties (including increases in both spheroid formation and in the aldehyde dehydrogenase 1 (ALDH1)high population). In contrast, S100A4 KO generally induced the opposite phenotypes, although it did not affect migration capability. In clinical OCCC samples, high S100A4 expression was associated with a low frequency of cleaved poly-(ADP-ribose) polymerase 1-positive apoptotic cells, a reduced proliferative rate, and expression of high ALDH1 and vimentin levels. In addition, a high S100A4 score was a significant (but not independent) prognostic factor in OCCC. Conclusions: Our findings suggest that S100A4 may be an unfavorable prognostic factor in OCCC, as it accelerates tumor progression and promotes chemoresistance through the modulation of proliferation, susceptibility to apoptosis, and EMT/CSC properties

ALK signaling cascade confers multiple advantages to glioblastoma cells through neovascularization and cell proliferation.

Anaplastic lymphoma kinase (ALK), which is a receptor tyrosine kinase, is essentially and transiently expressed in the developing nervous system. Here we examined the functional role of the ALK gene in glioblastomas (GBMs). In clinical samples of GBMs, high ALK expression without gene rearrangements or mutations was frequently observed in perivascular lesions, in contrast to the relatively low expression in the perinecrotic areas, which was positively correlated with N-myc and phosphorylated (p) Stat3 scores and Ki-67 labeling indices. ALK immunoreactivity was also found to be associated with neovascular features including vascular co-option and vascular mimicry. In astrocytoma cell lines, cells stably overexpressing full-length ALK showed an increase in expression of pStat3 and pAkt proteins, as well as hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A) mRNAs, in contrast to cells with knockdown of endogenous ALK which showed decreased expression of these molecules. Transfection of the constitutively active form of Stat3 induced an increase in HIF-1α promoter activity, and the overexpression of HIF-1α in turn resulted in enhancement of VEGF-A promoter activity. In addition, cells with overexpression or knockdown of ALK also showed a tendency toward increased and decreased proliferation, respectively, through changes in expression of pAkt and pStat3. Finally, ALK promoter was significantly activated by transfection of Sox4 and N-myc, which are known to contribute to neuronal properties. These findings therefore suggest that N-myc/Sox4-mediated ALK signaling cascades containing Stat3, Akt, HIF-1α, and VEGF-A confer multiple advantages to tumor growth through alterations in neovascularization and cell proliferation in GBMs

Robustness of polyisobutylene for friction coefficients between bearing surfaces of bolted joints

In bolted joints, clamp force must be accurately controlled to secure their reliability. However, the clamp force varies widely in each tightening because friction coefficients at thread surfaces and bearing surfaces vary in each tightening due to lubricants, configuration error of bolts, surface roughness, and surface hardness, among other things. In this study, we investigated the robustness of polyisobutylene and ISO VG46 machine oil during the tightening process for several parameters of tightening conditions. We especially focused on variations of the friction coefficient between bearing surfaces at an appropriate target clamp force of M8 bolt/nut assemblies and change rates of the friction coefficients from the middle to the end of the appropriate target clamp force. Results showed that the friction coefficients at the target clamp force varied widely if ISO VG46 machine oil was used as a lubricant. In contrast, the variations of the friction coefficients in which polyisobutylene was used for tightening were small. Results also showed that the friction coefficients invariably decreased about 20% from the middle to the end of the target clamp force if ISO VG46 machine oil was used for the lubricant. However, if polyisobutylene was used, the friction coefficients were almost constant for all tightening instances. </jats:p