LGR5 is an independent prognostic factor in Stages II and III of PD-AC. Although PD-AC has a poor prognosis [7], the related factors are not well understood. PD-AC has solid and non-solid subtypes. The prognosis of non-solid with fibrosis is poor [10]. In our study, most PD-AC cases were non-solid, but no clear difference was shown in the prognosis of both non-solid and solid subtypes. LGR5 is also a promising gastric cancer CSC marker, and high LGR5 expression in the poor prognosis group may suggest involvement of CSCs in the prognosis. Therefore, LGR5 may be a therapeutic target in PD-AC and may improve PD-AC prognosis.
The migration ability and EMT are increased in poorly differentiated gastric cancer [11]. The cause of a poor prognosis at high LGR5 expression may be related to the histological features of poorly differentiated cancer represented by migration ability acquisition and EMT-related protein expression and LGR5 expression. Cancer cell migration is known to affect prognosis in gastric cancer[11]. Additionally, LGR5 expression, although not in the stomach, is related to migration ability and EMT [12]. In our study, the correlation between vascular invasion and high LGR5 expression may support an association of LGR5 expression with EMT. High expression of LGR5 and EMT was reported to be correlated in gastric cancer [13]. Furthermore, Zhang et al. reported that RSPO2, a ligand of LGR5, promotes EMT in gastric cancer cells by activating WNT/β-catenin signaling via LGR5 [14]. Therefore, elucidation of the relationship between LGR5 and RSPO2 in PD-AC may lead to the development of new therapeutic methods and an improved prognosis for PD-AC.
Although some reports have indicated that high LGR5 expression is associated with a poor prognosis[15] [16], others have reported that high LGR5 expression correlates with a good prognosis in RNAscope studies, which are considered to have high reliability [17] [18]. The expression of LGR5 in the tumors of various organs has been widely discussed; most of them are the results of studies evaluated by immunostaining. The results of immunostaining may be controversial and uncertain. We pointed out that high LGR5 expression might be a poor prognostic factor in breast cancer by RNAscope examination [19]. Further studies are needed regarding the prognostic impact of LGR5 RNA expression.
Several reports have investigated LGR5 expression in gastric cancer. One has indicated no significant difference in the OS of gastric cancer when examined using RNAscope [20]. Although evaluated by immunostaining, LGR5 overexpression was reported to be significantly associated with an increased risk of death in gastric cancer patients in a review of LGR5 expression in gastric cancer [21]. In addition, Bu et al. reported that LGR5 expression is associated with a favorable prognosis, although it was limited to Stages I and II [22]. Furthermore, LGR5 expression was associated with a high stage and lymph node metastasis [20]. Although no association was found between high LGR5 expression and the histological type, as pointed out in a previous review [20], Xi et al. reported that high LGR5 expression is associated with poorly differentiated cancer [23]. However, Bu et al. reported that LGR5 is highly expressed in well-differentiated cancer [22]. Additionally, in studies using RNAscope, high LGR5 expression is correlated with well-differentiated cancer [24]. However, there is no comparison between LGR5 expression and prognosis in PD-AC using RNAscope, and the association between high LGR5 expression and poor prognosis in poorly differentiated cancer is a new finding.
The tendency for low LGR5 expression in EBV expression may be a feature of EBV-associated gastric cancer. EBV-associated gastric cancer is recognized as a distinct type of gastric cancer, according to a novel molecular pathological classification [25] and is recognized as a cancer with a good prognosis [26]. The Cancer Genome Atlas Research Network reports that gastric cancer is divided into four types [25]. Therefore, it is necessary to analyze LGR5 expression in each, hoping that further knowledge will be accumulated in the future.
Our study possesses some limitations. This study had a relatively small sample size, which may have led to unreliable estimates. LGR5 expression and migration must be investigated in cultured cells; additionally, LGR5 expression must be analyzed in EBV-infected cells.