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

Abstract

Abstract. 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.

Serum HER2 as a predictive biomarker for tissue HER2 status and prognosis in patients with gastric cancer

“…HER2 IHC was performed as described previously[18]. In brief, tumor specimens were fixed in 10% neutral-buffered formalin overnight and embedded in paraffin blocks.…”

Prognostic significance of leucine-rich-repeat-containing G-protein-coupled receptor 5, an intestinal stem cell marker, in gastric carcinomas

“…For GCs, previous studies have reported inconsistent results. Xi et al [24] showed that LGR5-positive patients had a significantly shorter survival time than LGR5-negative patients. On the other hand, Bauer et al [36] suggested that LGR5 mRNA expression was not a prognostic marker in GCs even though LGR5 expression increased in tumors after neoadjuvant chemotherapy.…”

“…In colorectal cancers, the prognostic value of LGR5 was extensively studied and found to be statistically related to the reduced overall survival [22]. However, for GCs, only a limited number of studies have investigated LGR5 expression and its relevance in predicting clinical outcomes [17,23,24]. Previously, we specifically identified LGR5-expressing cells in normal gastric mucosa and intestinal metaplastic lesions as well as gastric adenomas by RNA in situ hybridization (ISH) [25].…”

The prognostic role of Leucine-rich repeat-containing G-protein-coupled receptor 5 in gastric cancer: A systematic review with meta-analysis

“…Several studies have described the relationship between LGR5 expression and prognosis in gastric cancer [16][17][18][19][20][21]. These reports were inconsistent, however, with several studies drawing statistically insignificant results [17], and in certain cases, completely opposite results [16].…”