Oncotarget

Research Papers:

The roles of tricellular tight junction protein lipolysis-stimulated lipoprotein receptor in malignancy of human endometrial cancer cells

Hiroshi Shimada _, Seiro Satohisa, Takayuki Kohno, Syunta Takahashi, Tsubasa Hatakeyama, Takumi Konno, Mitsuhiro Tsujiwaki, Tsuyoshi Saito and Takashi Kojima

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Oncotarget. 2016; 7:27735-27752. https://doi.org/10.18632/oncotarget.8408

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Abstract

Hiroshi Shimada1,3, Seiro Satohisa1, Takayuki Kohno3, Syunta Takahashi3, Tsubasa Hatakeyama3, Takumi Konno3, Mitsuhiro Tsujiwaki2, Tsuyoshi Saito1, Takashi Kojima3

1Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan

2Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan

3Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan

Correspondence to:

Takashi Kojima, e-mail: [email protected]

Keywords: endometrial cancer, tricellular tight junctions, LSR, leptin, adiponectin

Received: January 15, 2016     Accepted: March 16, 2016     Published: March 28, 2016

ABSTRACT

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.


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