Leukemia inhibitory factor promotes gastric cancer cell proliferation, migration, and invasion via the LIFR-Hippo-YAP pathway.

The long-term outcome of gastric cancer (GC) patients remains unsatisfactory despite some recent improvements. Leukemia inhibitory factor (LIF) is a prognostic biomarker for some solid tumors, however its role in GC remains unknown. In this study, we demonstrated that LIF and LIF receptor (LIFR) are overexpressed in GC tissues and established that a correlation exists between them. LIF and LIFR expression are associated with tumor differentiation, lymphovascular invasion, tumor stage, lymph node metastasis, and pTNM stage, indicating that they may be useful prognostic factors. LIF promoted GC cell proliferation, colony formation, invasion, migration, and tumor growth; it also promoted cell cycle progression and inhibited apoptosis; and knocking out the LIFR gene reversed the effects of LIF. LIF inhibited the activity of the Hippo pathway, resulting in reduced phosphorylation of YAP, increased YAP nuclear translocation, and increased cell proliferation. Finally, silencing YAP mRNA expression suppressed cell proliferation. Overall, the results demonstrate that LIF promotes the malignant biological behavior of GC cells through LIFR-Hippo-YAP signaling. LIF may therefore be a useful biomarker for GC.

[Corrigendum] Increased expression of Lgr5 is associated with chemotherapy resistance in human gastric cancer.

An interested reader drew to the attention of the Journal that the western blot featured in Fig. 3B of the above paper also appeared as Fig. 3D in the following publication, featuring many of the same authors: Xi HQ, Cai AZ, Wu XS et al: Leucine­rich repeat­containing G­protein­coupled receptor 5 is associated with invasion, metastasis, and could be a potential therapeutic target in human gastric cancer. Br J Cancer 110: 2011­2020, 2014. After having consulted the authors about this matter, they conceded that there was a data sharing violation here, and that the image should not have been reproduced in the above article without having received the prior permission of the British Journal of Cancer. This permission has now been sought after and obtained, and Fig. 3 is reproduced opposite, now including the appropriate credit for the original source of Fig. 3B. The authors apologize to the Editors of the British Journal of Cancer and Oncology Reports, and to the readership for any inconvenience caused. [the original article was published in Oncology Reports 32: 181­188, 2014; DOI: 10.3892/or.2014.3204].

Palliative Therapy for Gastric Outlet Obstruction Caused by Unresectable Gastric Cancer: A Meta-analysis Comparison of Gastrojejunostomy with Endoscopic Stenting.

BACKGROUND: Gastrojejunostomy (GJJ) and endoscopic stenting (ES) are palliative treatments for gastric outlet obstruction (GOO) caused by gastric cancer. We compared the outcomes of GJJ with ES by performing a meta-analysis. METHODS: Clinical trials that compared GJJ with ES for the treatment of GOO in gastric cancer were included in the meta-analysis. Procedure time, time to resumption of oral intake, duration of hospital stay, patency duration, and overall survival days were compared using weighted mean differences (WMDs). Technical success, clinical success, procedure-related mortality, complications, the rate of re-obstruction, postoperative chemotherapy, and reintervention were compared using odds ratios (OR s). RESULTS: Nine studies were included in the analysis. Technical success and clinical success were not significantly different between the ES and GJJ groups. The ES group had a shorter procedure time (WMD = -80.89 min, 95% confidence interval [CI] = -93.99 to -67.78,P < 0.001), faster resumption of oral intake (WMD = -3.45 days, 95% CI = -5.25 to -1.65,P < 0.001), and shorter duration of hospital stay (WMD = -7.67 days, 95% CI = -11.02 to -4.33,P < 0.001). The rate of minor complications was significantly higher in the GJJ group (OR = 0.13, 95% CI = 0.04-0.40,P < 0.001). However, the rates of major complications (OR = 6.91, 95% CI = 3.90-12.25,P < 0.001), re-obstruction (OR= 7.75, 95% CI = 4.06-14.78,P < 0.001), and reintervention (OR= 6.27, 95% CI = 3.36-11.68,P < 0.001) were significantly lower in the GJJ group than that in the ES group. Moreover, GJJ was significantly associated with a longer patency duration (WMD = -167.16 days, 95% CI = -254.01 to -89.31,P < 0.001) and overall survival (WMD = -103.20 days, 95% CI = -161.49 to -44.91, P= 0.001). CONCLUSIONS: Both GJJ and ES are effective procedures for the treatment of GOO caused by gastric cancer. ES is associated with better short-term outcomes. GJJ is preferable to ES in terms of its lower rate of stent-related complications, re-obstruction, and reintervention. GJJ should be considered a treatment option for patients with a long life expectancy and good performance status.

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

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/ß-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 ß-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 full­length LKB1 transfection. In vitro and in vivo proliferation was inhibited in LKB1-overexpressing GC cells compared with the control cells. Yap and ß-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 ß-catenin was reversed by the silencing of LKB1 or Yap with shRNAs in LKB1-overexpressing GC cells. Moreover, Yap and ß-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 ß-catenin.

Increased expression of Lgr5 is associated with chemotherapy resistance in human gastric cancer.

Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5), a marker of adult stem cells and cancer stem cells, plays important roles in tumor progression. Furthermore, Lgr5 also contributes to chemoradiotherapy resistance. However, the function of Lgr5 in the prediction of preoperative chemotherapy efficacy has not been reported. We evaluated the potential of Lgr5 in predicting tumor response and overall survival in advanced gastric cancer treated with preoperative chemotherapy. The association between Lgr5 and chemotherapy resistance was also investigated in gastric cancer cell lines. Hematoxylin and eosin staining and immunohistochemical analysis of Lgr5 expression were performed in 68 cases of gastric cancer treated with preoperative chemotherapy. Lgr5 expression was specifically silenced in the AGS gastric cancer cell lines by RNA interference. Levels of Lgr5 mRNA and protein in cell lines were detected by quantitative reverse transcription-polymerase chain reaction or western blotting. Cell viability was evaluated by an MTT assay. Cell apoptosis was assessed by Annexin V-FITC/propidium iodide dual staining analysis. We found that Lgr5 expression was significantly associated with tumor regression grade after preoperative chemotherapy. The rate of positive Lgr5 expression was significantly higher in patients with poor tumor regression compared with those exhibiting tumor regression (P=0.001). Lgr5-positive patients had a significantly shorter survival time than Lgr5-negative patients (P=0.001). Inhibition of Lgr5 expression with small interfering RNA increased the sensitivity of AGS gastric cancer cells to chemotherapy. Our findings suggest that Lgr5 expression may be implicated in the chemoresistance of gastric cancer cells and is a potential novel biomarker for predicting response to chemotherapy and prognosis in gastric cancer patients, and may also represent a potential new therapeutic target for cancer therapy.

[Choice and reasonable application of staplers for gastrointestinal surgery].

Digestive tract reconstruction is the main part of gastrointestinal surgery. With the rapid development of technology and widely application in stapling device, more and more surgeons are using stapled anastomosis. Stapled anastomosis is associated with shorter operating time and hospital stay than hand-sewn anastomosis. However, it is not easy to select suitable ones from various staplers and use them correctly. Choice and reasonable application of staplers for anastomosis in gastrointestinal surgery are summarized and evaluated in this article.