CLDN4 silencing promotes proliferation and reduces chemotherapy sensitivity of gastric cancer cells through activation of the PI3K/Akt signalling pathway.

New Findings: What is the central question of this study? What is the influence of the interaction between the matrix protein CLDN4 and the PI3K/Akt signalling pathway on tumour progression and chemotherapy sensitivity in gastric cancer? What is the main finding and its importance? Silencing of CLDN4 can promote the growth and proliferation of gastric cancer cells by activating the PI3K/Akt signalling pathway, and thus reduce the sensitivity of gastric cancer cells to chemotherapy.

Abstract: Gastric cancer (GC) is one of the most common cancers worldwide and has a high mortality rate, accompanied by metastasis. Claudins (CLDNs) are major tight-junction proteins that mediate cellular polarity and differentiation. In the present study, we investigated the role of claudin 4 (CLDN4) in modulating cell proliferation and chemotherapeutic sensitivity in GC. Immunohistochemistry and RT-qPCR were initially used to detect the expression of CLDN4 in cancer tissues and adjacent normal tissues collected from GC patients. GC cell lines with the highest and the lowest CLDN4 expression were selected for subsequent experiments. The effects of CLDN4 on GC cell chemosensitivity, proliferation, invasion, migration, apoptosis and tumourigenic capacity were evaluated by conducting gain- and loss-of-function studies of CLDN4. Expression of CLDN4 was significantly decreased in GC tissues and cell lines compared to adjacent normal tissues or gastric epithelial cells. Silencing of CLDN4 increased the extent of PI3K and Akt phosphorylation, and also the proliferation, migration, invasion and tumourigenesis of GC cells; at the same time apoptosis and the sensitivity of GC cells to chemotherapy were reduced. In conclusion, CLDN4 may play a pivotal role in attenuating GC cell proliferation and enhancing sensitivity of GC cells to chemotherapy by inactivating the PI3K/Akt signalling pathway.