Identification of AQP3 and CD24 as biomarkers for carcinogenesis of gastric intestinal metaplasia.

Gastric intestinal metaplasia (GIM) is a precancerous gastric carcinoma (GC) lesion with pivotal roles in carcinogenesis. CD24, LGR5 and Ki67 are expressed in GIM; we previously demonstrated that aquaporin 3 (AQP3) is expressed in goblet cells and is positively correlated with GIM severity. However, the relationships of AQP3 with GIM classification and with other proteins, and their roles in the transition from GIM to gastric carcinoma (GC) remain unknown. Sixteen patients with intestinal-type GC were enrolled in this study. GIM was determined according to the updated Sydney system; GIM classification was determined via HID-AB staining, and AQP3, CD24, LGR5 and Ki67 expression were determined by immunohistochemistry. Type III GIM was more prevalent around the GC and displayed a positive association with GIM severity. CD24 was found in GIM, but LGR5 and Ki67 were found in tissues regardless of GIM. AQP3 expression showed significant correlation to type III GIM. CD24 expression was correlated with the marked GIM and incomplete GIM, while LGR5 expression decreased with GIM aggravation and did not have relationship with classification of GIM. However, Ki67 presented no association with GIM grade or classification. These observations identify AQP3 and CD24 as biomarkers for carcinogenesis of GIM, and may provide a precise strategy for screening at-risk candidates with GIM.

Clinicopathologic and prognostic characteristics of alpha-fetoprotein-producing gastric cancer.

Alpha-fetoprotein-producing gastric cancer (AFPGC) accounts for 1.5%-7.1% of all gastric cancer cases. Compared with other types of gastric cancer, AFPGC is more aggressive and prone to liver and lymph node (LN) metastasis, with extremely poor prognosis. To improve understanding of AFPGC we reviewed a consecutive series of 82 AFPGC patients and investigated the prognostic factors. The incidence of AFPGC among our gastric cancer patients was 1.95%, and 29.27% of AFPGCs were diagnosed with metastasis at the time of presentation, mainly liver metastasis. The serum AFP level of patients with AFPGC was significantly associated with tumor differentiation. Histologically, these AFPGC patients were composed of 34.55% hapatiod type, 58.18% fetal gastrointestinal type, 9.09% yolk sac tumor-like type, and 14.55% mixed type. Patient gender, tumor differentiation, Lauren classification, and number of metastatic lymph nodes showed significant differences among these four subtypes. The overall survival time was 42.02 months and the 3-year cumulative survival rate was 53.13%. Age, American Joint Committee on Cancer (AJCC) TNM staging classification (TNM stage), serum AFP level, and surgery were prognostic factors for overall survival; however, TNM stage was the only independent risk factor for prognosis of AFPGC. In short, AFPGC is a rare, unique, and heterogeneous entity, and its proper identification and treatment remain a challenge. More attention should be paid to AFPGC to improve patient care and the dismal prognosis.

Aquaporin 3 facilitates chemoresistance in gastric cancer cells to cisplatin via autophagy.

Cisplatin (cDDP) remains one of the first-line chemotherapeutic agents for gastric cancer (GC) treatment, and resistance to cDDP is the major limitation in its clinical application. Mechanisms of cDDP resistance have been shown to be varied and complicated. Aquaporin 3 (AQP3) has been demonstrated to be overexpressed in GC tissues and is thought to be involved in GC carcinogenesis and progression. However, the role of AQP3 in chemosensitivity of GC to cytotoxic agents remains unknown. In this study, we show that AQP3 overexpression induced resistance to cDDP in AGS cells (P<0.05), and AQP3 knockdown increased the chemosensitivity in MGC803 and SGC7901 cells (P<0.05). Moreover, cDDP treatment enhanced AQP3 expression in MGC803, SGC7901 and AGS cells. AQP3 overexpression promoted the conversion of LC3-I to LC3-II in AGS cells, whereas AQP3 knockdown inhibited this conversion in MGC803 and SGC7901 cells. AQP3 upregulation increased Atg5 and Beclin-1 expression, and inhibited P62 expression in AGS cells, whereas AQP3 knockdown showed the opposite results in MGC803 and SGC7901 cells. Chloroquine (CQ), an autophagy inhibitor, enhanced the cytotoxicity of cDDP in GC cells, and CQ reversed the chemoresistance to cDDP caused by AQP3 overexpression in GC cells. Together, our data demonstrate that AQP3 facilitates cisplatin resistance in gastric cancer cells via autophagy, and suggest that the development of AQP3-based tumor therapeutics could play a key role in future GC treatment strategies.

Aquaporin 3 promotes the stem-like properties of gastric cancer cells via Wnt/GSK-3ß/ß-catenin pathway.

Cancer stem cells (CSCs) are believed to contribute to the tumor growth in gastric carcinoma (GC), a common lethal malignancy. This study investigated the effect of aquaporin 3 (AQP3) on stem-like properties of human GC cells. Elevated AQP3 expression was associated with CD44 expression in human GC specimens. Expression of AQP3 and that of CD44 positively correlated with Lauren classification, lymph node metastasis, and lymphovascular invasion. Altering the AQP3 expression had pronounced effects on the tumorigenic potential and self-renewal capacity of the gastric cancer cell lines SGC7901, MGC803, and AGS, both in vitro and in vivo. Overexpression of AQP3 induced CD44 expression and activation of the ß-catenin signaling pathway, whereas silencing AQP3 expression using short hairpin RNA had the opposite effect. Furthermore, pharmacological inhibition of GSK-3ß using LiCl impaired the effect of AQP3 knockdown in CSCs, whereas the inhibition of the Wnt/ß-catenin pathway by XAV939 blocked the effect of AQP3 overexpression. These results demonstrate that AQP3 promotes stem-like properties of human GC cells by activating the Wnt/GSK-3ß/ß-catenin signaling pathway.