Lipolysis-stimulated lipoprotein receptor (LSR) is a unique molecule of tricellular contacts of normal and cancer cells. We investigated how the loss of LSR induced cell migration, invasion and proliferation in endometrial cancer cell line Sawano. mRNAs of amphiregulin (AREG) and TEA domain family member 1 (TEAD1) were markedly upregulated by siRNA-LSR. In endometrial cancer tissues, downregulation of LSR and upregulation of AREG were observed together with malignancy, and Yes-associated protein (YAP) was present in the nuclei. siRNA-AREG prevented the cell migration and invasion induced by siRNA-LSR, whereas treatment with AREG induced cell migration and invasion. LSR was colocalized with TRIC, angiomotin (AMOT), Merlin and phosphorylated YAP (pYAP). siRNA-LSR increased expression of pYAP and decreased that of AMOT and Merlin. siRNA-YAP prevented expression of the mRNAs of AREG and TEAD1, and the cell migration and invasion induced by siRNA-LSR. Treatment with dobutamine and 2-deoxy-D-glucose and glucose starvation induced the pYAP expression and prevented the cell migration and invasion induced by siRNA-LSR. siRNA-AMOT decreased the Merlin expression and prevented the cell migration and invasion induced by siRNA-LSR. The loss of LSR promoted cell invasion and migration via upregulation of TEAD1/AREG dependent on YAP/pYAP and AMOT/Merlin in human endometrial cancer cells.

Lipolysis-stimulated lipoprotein receptor (LSR) has been identified as a novel molecular constituent of tricellular contacts that have a barrier function for the cellular sheet. LSR recruits tricellulin (TRIC), which is the first molecular component of tricellular tight junctions. Knockdown of LSR increases cell motility and invasion of certain cancer cells. However, the behavior and the roles of LSR in endometrial cancer remain unknown. In the present study, we investigated the behavior and roles of LSR in normal and endometrial cancer cells in vivo and in vitro. In endometriosis and endometrial cancer, LSR was observed not only in the subapical region but also throughout the lateral region as well as in normal endometrial epithelial cells in the secretory phase, and LSR in the cancer was reduced in correlation with the malignancy. Knockdown of LSR by the siRNA in cells of the endometrial cancer cell line Sawano, induced cell migration, invasion and proliferation, while TRIC relocalized from the tricellular region to the bicellular region at the membrane. In Sawano cells and normal HEEs, a decrease of LSR induced by leptin and an increase of LSR induced by adiponectin and the drugs for type 2 diabetes metformin and berberine were observed via distinct signaling pathways including JAK2/STAT. In Sawano cells, metformin and berberine prevented cell migration and invasion induced by downregulation of LSR by the siRNA and leptin treatment. The dissection of the mechanism in the downregulation of endometrial LSR during obesity is important in developing new diagnostic and therapy for endometrial cancer.

Junctional adhesion molecule-A (JAM-A

Disruption of nasal epithelial tight junctions (TJs) and ciliary dysfunction are found in patients with chronic rhinosinusitis (CRS) and nasal polyps (NPs), along with an increase of p63-positive basal cells and histone deacetylase (HDAC) activity. To investigate these mechanisms, primary cultures of HNECs transfected with human telomerase reverse transcriptase (hTERT-HNECs) were transfected with siRNAs of TAp63 and ΔNp63, treated with the NF-kB inhibitor curucumin and inhibitors of HDACs, and infected with respiratory syncytial virus (RSV). In TERT-HNECs, knockdown of p63 by siRNAs of TAp63 and ΔNp63, induced claudin-1 and -4 with Sp1 activity and enhanced barrier and fence functions. The knockdown of p63 enhanced the number of microvilli with the presence of cilia-like structures. Treatment with curcumin and inhibitors of HDACs, or infection with RSV prevented expression of p63 with an increase of claudin-4 and the number of microvilli. The knockdown or downregulation of p63 inhibited phospho-p38MAPK, and the p38MAPK inhibitor downregulated p63 and upregulated the barrier function. Thus, epithelial barrier and ciliogenesis of nasal epithelium are regulated in a p63-negative manner in normal and upper airway diseases. Understanding of the regulation of p63/p38 MAPK/NF-κB may be important in the therapy for airway allergy and its drug delivery system.

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