TMTC1 promotes invasiveness of ovarian cancer cells through integrins ß1 and ß4.

Ovarian cancer is the most lethal gynecological malignancy and is characterized by peritoneal disseminated metastasis. Although O-mannosyltransferase TMTC1 is highly expressed by ovarian cancer, its pathophysiological role in ovarian cancer remains unclear. Here, immunohistochemistry showed that TMTC1 was overexpressed in ovarian cancer tissues compared with adjacent normal ovarian tissues, and high TMTC1 expression was associated with poor prognosis in patients with ovarian cancer. Silencing TMTC1 reduced ovarian cancer cell viability, migration, and invasion in vitro, as well as suppressed peritoneal tumor growth and metastasis in vivo. Moreover, TMTC1 knockdown reduced cell-laminin adhesion, which was associated with the decreased phosphorylation of FAK at pY397. Conversely, TMTC1 overexpression promoted these malignant properties in ovarian cancer cells. Glycoproteomic analysis and Concanavalin A (ConA) pull-down assays showed that integrins ß1 and ß4 were novel O-mannosylated protein substrates of TMTC1. Furthermore, TMTC1-mediated cell migration and invasion were significantly reversed by siRNA-mediated knockdown of integrin ß1 or ß4. Collectively, these results suggest that TMTC1-mediated invasive behaviors are primarily through integrins ß1 and ß4 and that TMTC1 is a potential therapeutic target for ovarian cancer.

GALNT2 promotes invasiveness of colorectal cancer cells partly through AXL.

GalNAc-type O-glycosylation and its initiating GalNAc transferases (GALNTs) play crucial roles in a wide range of cellular behaviors. Among 20 GALNT members, GALNT2 is consistently associated with poor survival of patients with colorectal cancer in public databases. However, its clinicopathological significance in colorectal cancer remains unclear. In this study, immunohistochemistry showed that GALNT2 was overexpressed in colorectal tumors compared with the adjacent nontumor tissues. GALNT2 overexpression was associated with poor survival of colorectal cancer patients. Forced expression of GALNT2 promoted migration and invasion as well as peritoneal metastasis of colorectal cancer cells. In contrast, GALNT2 knockdown with siRNAs or knockout with CRISPR/Cas9 system suppressed these malignant properties. Interestingly, we found that GALNT2 modified O-glycans on AXL and determined AXL levels via the proteasome-dependent pathway. In addition, the GALNT2-promoted invasiveness was significantly reversed by AXL siRNAs. These findings suggest that GALNT2 promotes colorectal cancer invasion at least partly through AXL.

C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin αv.

Pancreatic adenocarcinoma (PDAC) is a leading cause of cancer-related death. Altered glycosylation contributes to tumor progression and chemoresistance in many cancers. C1GALT1 is the key enzyme controlling the elongation of GalNAc-type O-glycosylation. Here we showed that C1GALT1 was overexpressed in 85% (107/126) of PDAC tumors compared with adjacent non-tumor tissues. High expression of C1GALT1 was associated with poor disease-free and overall survival (n = 99). C1GALT1 knockdown using siRNA suppressed cell viability, migration, and invasion as well as increased gemcitabine sensitivity in PDAC cells. In contrast, C1GALT1 overexpression enhanced cell migration and invasion. In subcutaneous and pancreatic orthotopic injection models, C1GALT1 knockdown decreased tumor growth and metastasis of PDAC cells in NOD/SCID mice. Mechanistically, C1GALT1 knockdown dramatically suppressed cell-extracellular matrix (ECM) adhesion, which was associated with decreased phosphorylation of FAK at Y397/Y925 and changes in O-glycans on integrins including the ß1, αv, and α5 subunits. Using functional blocking antibodies, we identified integrin αv as a critical factor in C1GALT1-mediated invasiveness of PDAC cells. In conclusion, this study not only reveals that C1GALT1 could be a potential therapeutic target for PDAC but also provides novel insights into the role of O-glycosylation in the α subunits of integrins.

The effect of cushion properties on skin temperature and humidity at the body-support interface.

The purpose of this study is to explore the effects of various cushions on skin temperature and moisture at the body-seat interface during a 2-hour period of continuous sitting. Seventy-eight participants were randomly assigned to sit on one of the three types of wheelchair cushions for unrelieved sitting for over 2 hours. Skin temperature and relative humidity (RH) were measured under the subjects' ischial tuberosities and thighs bilaterally with digital temperature and humidity sensors. Data were collected before sitting and at 15-minute intervals thereafter. Participants sitting on foam-fluid hybrid cushions showed significantly lower skin temperatures than those sitting on air-filled and foam cushions (p < 0.05), but RH did not differ significantly among the cushions (p = 0.97). The three cushions produced a similar increasing trend in RH over time and RH reached a plateau during the 2-hour sitting period. To select the appropriate wheelchair cushion, the microclimate (heat and moisture control) between the body-seat interface should be considered as well as pressure distribution. In comparison with foam-fluid hybrid cushions, the air-filled rubber and foam cushions tended to increase skin temperature by several degrees after prolonged sitting. However, cushion materials did not have significant differences in moisture accumulations.