Nuclear distribution of claudin-2 increases cell proliferation in human lung adenocarcinoma cells

Abstract

Claudin-2 is expressed in human lung adenocarcinoma tissue and cell lines, although it is absent in normal lung tissue. However, the role of claudin-2 in cell proliferation and the regulatory mechanism of intracellular distribution remain undefined. Proliferation of human adenocarcinoma A549 cells was decreased by claudin-2 knockdown together with a decrease in the percentage of S phase cells. This knockdown decreased the expression levels of ZONAB and cell cycle regulators. Claudin-2 was distributed in the nucleus in human adenocarcinoma tissues and proliferating A549 cells. The nuclear distribution of ZONAB and percentage of S phase cells were higher in cells exogenously expressing claudin-2 with a nuclear localization signal than in cells expressing claudin-2 with a nuclear export signal. Nuclear claudin-2 formed a complex with ZO-1, ZONAB, and cyclin D1. Nuclear distribution of S208A mutant, a dephosphorylated form of claudin-2, was higher than that of wild type. We suggest that nuclear distribution of claudin-2 is up-regulated by dephosphorylation and claudin-2 serves to retain ZONAB and cyclin D1 in the nucleus, resulting in the enhancement of cell proliferation in lung adenocarcinoma cells.

Nuclear expression of claudin‑3 in human colorectal adenocarcinoma cell lines and tissues

“…The cytoplasmic expression of claudin-1 in metastatic melanoma cells was also shown to be critical for increased malignancy (27,40). In addition, nuclear distribution of claudin-2 resulted in enhanced proliferation in human lung adenocarcinoma cells (34). As aforementioned, the cellular distribution of claudins has been reported in several types of cancer (41); however, the pathophysiological functions of nuclear claudins have not yet been determined.…”

“…The predominant cytoplasmic and nuclear localization of claudin-1 was revealed to exhibit anti-apoptotic activity in nasopharyngeal carcinoma cells (28). In addition, the nuclear distribution of claudin-2 has been shown to contribute to enhancing the proliferation of lung adenocarcinoma cells (34). However, the mechanisms underlying the different functions of claudins in tumorigenesis have not been clearly defined to date.…”

Claudins and cancer: Fall of the soldiers entrusted to protect the gate and keep the barrier intact

“…Similarly, nuclear localization of claudin-2 in correlation with the cellular proliferation has been demonstrated [26]. Recent studies further suggest that claudin expression may even be distinct within specific subtypes of the cancers: for example, claudin-4 expression is downregulated in grade 1 ductal carcinoma of the breast compared to normal mammary epithelial cells [27], whereas it is significantly upregulated in basal-like breast cancer [28].…”

Systems Proteomics View of the Endogenous Human Claudin Protein Family

“…1,14,70 Nuclear localization of claudins has also been observed. 1,10,20,71–73 Roles for nonjunctional claudins are not well understood, although the literature correlating nuclear claudin localization with tumor metastasis suggests roles for these claudin pools in regulating cell growth, division, and migration. 61,74–78 …”