Keratin 18 induces proliferation, migration, and invasion in gastric cancer via the MAPK signalling pathway
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
Authors: Wang, Peng-Bin; Chen, Yan; Ding, Guang-Rong; Du, Hong-Wei; Fan, Hong-Yan
Abstract
Purpose Keratin 18 (KRT18) is a cytoskeleton protein that plays a key role in multiple cancers. The present study aims to further investigate the roles of KRT18 in gastric cancer (GC) tissues and cells. Methods The KRT18 protein expression levels of GC tissues and cells were detected using immunohistochemistry and western blot. The relationship between KRT18 expression levels and the prognosis of GC patients was further analyzed. To explore this relationship, small interfering RNA (siRNA) was used to inhibit the endogenous expression of KRT18 in GC cells. Furthermore, the effects of KRT18 on the proliferation, invasion, migration, and apoptosis of GC cells were analyzed in vitro. In addition, the role of KRT18 in GC-specific processes was investigated. Results Keratin 18 expression was shown to be up-regulated in GC tissues and associated with poor prognosis. Following KRT18 silencing with siRNA, the proliferation, invasion, and migration ability of GC cells were significantly inhibited, while the apoptotic process was promoted. Furthermore, the activation of the MAPK signalling pathway was identified as the potential mechanism through which KRT18 influenced GC processes. Conclusions Keratin 18 plays a cancer-promoting role and might be a potential therapeutic target in the treatment of GC.
Xanthohumol Inhibits the Growth of Keratin 18-Overexpressed Esophageal Squamous Cell Carcinoma in vitro and in vivo
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
Authors: Yin, Shuying; Song, Mengqiu; Zhao, Ran; Liu, Xuejiao; Kang, Woo Kyu; Lee, Jeong Min; Kim, Young Eun; Zhang, Chengjuan; Shim, Jung-Hyun; Liu, Kangdong; Dong, Zigang; Lee, Mee-Hyun
Abstract
Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related death worldwide. Xanthohumol is a prenylated flavonoid isolated from hops. Although xanthohumol has been reported to exert anti-obesity, hypoglycemic, anti-hyperlipidemia and anti-cancer activities, the mechanisms underlying its chemotherapeutic activity are yet to be elucidated. In the present study, we found that xanthohumol inhibited ESCC cell proliferation in vitro and in vivo by targeting keratin (KRT)-18. Xanthohumol suppressed the proliferation, foci formation, and anchorage-independent colony growth of KYSE30 cells. Using xanthohumol-sepharose conjugated bead pull-down and mass/mass analysis, we found that KRT18 is a novel target of xanthohumol in KYSE30 cells. KRT18 protein was highly expressed in patient ESCC tissues compared to adjunct tissues. Anti-proliferative activity of xanthohumol was abrogated or enhanced according to the knockdown or overexpression of KRT18 protein, respectively. Xanthohumol also induced apoptosis and cell cycle arrest at G1 phase which was associated with the modulation of expression of related makers including cyclin D1, cyclin D3, and cleaved-PARP, Bcl-2, cytochrome c and Bax. While xanthohumol attenuated KRT18 protein expression, it failed to cause any change in the KRT18 mRNA level. Furthermore, oral administration of xanthohumol decreased tumor volume and weight in patient-derived xenografts (PDXs) tumors having overexpressed KRT18. Overall these results suggest that xanthohumol acts as a KRT18 regulator to suppress the growth of ESCC.