LKB1 inhibits the proliferation of gastric cancer cells by suppressing the nuclear translocation of Yap and β-catenin

Abstract

Liver kinase B1 (LKB1) is known to suppress the proliferation, energy metabolism and mesenchymal transition of various cancer cells, and is involved in the regulation of Hippo-Yes-associated protein (Yap) and the Wnt/β-catenin signaling pathways. However, the role of LKB1 in gastric cancer (GC) was not fully understood. Thus, in the present study, we studied LKB1 and found that protein expression (0.37±0.061 vs. 0.59±0.108, P=0.006) and the protein ratio of p-Yap/Yap (0.179±0.085 vs. 0.8±0.126, P=0.001) were reduced in 54 gastric adenocarcinoma (GAC) tissues compared with the matched adjacent non-cancerous tissues, using western blotting and RT-qPCR assays. LKB1 expression was also observed decreased in 109 GAC tissues compared with 54 adjacent non-cancerous tissues (χ2=4.678, P=0.0306), and negatively correlated with the nuclear expression of Yap (r=-0.6997) and β-catenin (r=-0.3510), using immunohistochemical analysis. In GC patients, LKB1 expression was negatively associated with tumor size, tumor infiltration, lymph node metastasis and the TNM stage. LKB1 expression was determined to be positively correlated with longer overall survival of GC patients using Kaplan-Meier analysis (P=0.001). Subsequently, LKB1 expression in human GAC AGS cells was enhanced with a full‑length LKB1 transfection. In vitro and in vivo proliferation was inhibited in LKB1-overexpressing GC cells compared with the control cells. Yap and β-catenin expression were assessed by western blotting and RT-qPCR, and were found to be increased in the cytoplasm but decreased in the nucleus in LKB1-overexpressing GC cells compared with the control cells. The increase in cytoplasmic β-catenin was reversed by the silencing of LKB1 or Yap with shRNAs in LKB1-overexpressing GC cells. Moreover, Yap and β-catenin mRNA were barely altered by LKB1 overexpression. Thus, we concluded that LKB1 expression was reduced in GAC tissues but that it correlated positively with better prognosis for GC patients. LKB1 inhibits the proliferation of GC cells by suppressing the nuclear translocation of Yap and β-catenin.

Functional characterization of AMP-activated protein kinase signaling in tumorigenesis

“…The CCL2-mediated macrophage recruitment is enhanced in part due to the loss-of-function mutation on LKB1 , which partially explains the development of endometrial cancer [49]. Besides, LKB1 could likewise affect epithelial mesenchymal transition [50], Hippo/YAP signaling [51], proinflammatory transduction [52] as well as TGF-β pathway [53] to function as a tumor suppressor in multiple neoplasms.…”

LKB1 signaling is activated in CTNNB1‐mutated HCC and positively regulates β‐catenin‐dependent CTNNB1‐mutated HCC

“…Cross talk between Wnt/β-catenin and LKB1 signaling in both directions (β-catenin toward LKB1 and LKB1 toward β-catenin) has been described in many studies. It appears that the dialog depends on the context, developmental or oncogenic, with either a positive or a negative impact [15][16][17][18][19][20][21][22]. The molecular mechanisms involved are yet to be determined for all contexts.…”

“…However, this oncogenic function of LKB1 has already been observed in other settings [13,14]. In addition, numerous studies described molecular cross talk between LKB1 and the Wnt/β-catenin signaling pathway [15][16][17][18][19][20][21][22].…”

“…Cross talk between Wnt/β-catenin and LKB1 signaling has been described in several studies, with often conflicting results [15][16][17][18][19][20][21][22]. The first pioneering study showed LKB1 to be upstream of β-catenin signaling and to be required for full activation of β-catenin signaling in Xenopus development [15].…”

TAZ promotes cell growth and inhibits Celastrol-induced cell apoptosis

“…To date, there has been a considerable body of evidence that links YAP/TAZ to tumorigenicity in cancers. Overexpression of YAP is generally common in a wide variety of tumours, including colon cancer [ 29 ], lung cancer [ 10 ], gastric cancer [ 30 ], liver cancer [ 31 ] and breast cancer [ 8 ]. YAP can promote cell proliferation, inhibit cell apoptosis, lead to loss of cell contact inhibition and promote cell malignant transformation [ 32 ].…”