Carcinoma cells hijack the epithelial-mesenchymal transition (EMT) for tumor dissemination. Paired-related homeobox 1 (PRRX1) has been identified as a new EMT inducer. However, the function of PRRX1 in gastric cancer has not been elucidated. In this study, we observed that PRRX1 expression levels were upregulated and positively correlated with metastasis and EMT markers in human gastric cancer specimens. PRRX1 overexpression had distinct effects on the cell morphology, proliferation, migration and invasion of BGC823 and SGC7901 gastric cancer cells both in vitro and in xenografts. PRRX1 overexpression resulted in the regulation of the EMT molecular markers N-cadherin, E-cadherin and vimentin as well as the levels of intranuclear β-catenin and the Wnt/β-catenin target c-Myc. Furthermore, the inhibition of the Wnt/β-catenin pathway by XAV939 offset the effects of PRRX1 overexpression. These findings demonstrate that PRRX1 promotes EMT in gastric cancer cells through the activation of Wnt/β-catenin signaling and that PRRX1 upregulation is closely correlated with gastric cancer metastasis.

Peroxiredoxin 2 (Prdx2) is a member of the peroxiredoxin family, which is responsible for neutralizing reactive oxygen species. Prdx2 has been found to be elevated in several human cancer cells and tissues, including colorectal cancer (CRC), and it influences diverse cellular processes involving cells' survival, proliferation, and apoptosis, which suggests a possible role for Prdx2 in the maintenance of cancer cell. However, the mechanism by which Prdx2 modulates CRC cells' survival is unknown. The current study aimed to determine the effect of elevated Prdx2 on CRC cells and to further understand the underlying mechanisms. The results of this study showed that Prdx2 was upregulated in CRC tissues compared with the matched noncancer colorectal mucosa tissues and that Prdx2 expression was positively associated with tumor metastasis and the TNM stage. In the LoVo CRC cell line, Prdx2 was upregulated at both the RNA and protein levels compared with the normal FHC colorectal mucosa cell line. In addition, the LoVo CRC cell line was significantly more resistant to hydrogen peroxide (H₂O₂)-induced apoptosis because of a failure to activate pro-apoptotic pathways in contrast to Prdx2 knockdown cells. Suppression of Prdx2 using a lentiviral vector-mediated Prdx2-specific shRNA in the LoVo cell line restored H₂O₂ sensitivity. Our results suggested that Prdx2 has an essential role in regulating oxidation-induced apoptosis in CRC cells. Prdx2 may have potential as a therapeutic target in CRC.

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BackgroundMetastasis is a major threat to colorectal cancer (CRC) patients. We have reported that peroxiredoxin-2 (PRDX2) is associated with CRC invasion and metastasis. However, the mechanisms regulating PRDX2 expression remain unclear. We investigate whether microRNAs (miRNAs) regulate PRDX2 expression in CRC progression.MethodsQuantitative real-time polymerase chain reaction (qPCR) was used to measure microRNA-200b-3p (miR-200b-3p) expression. Immunohistochemistry (IHC) was performed to detect c-Myc and PRDX2 protein levels in CRC tissue samples (n = 97). Western blot was used to quantify PRDX2, c-Myc, AKT2/GSK3β pathway-associated proteins and epithelial-mesenchymal transition (EMT)-related proteins in CRC cells. Luciferase reporter assays were used to analyze the interaction between miR-200b-3p and 3′untranslated region (3′UTR) of PRDX2 mRNA and AKT2 mRNA as well as c-Myc and the miR-200b-3p promoter. Chromatin immunoprecipitation (ChIP) assay was used to evaluate binding of c-Myc to the miR-200b-3p promoter. Invasive assay and metastatic model were used to assess invasive and metastatic capacities of CRC cells in vitro and in vivo. Moreover, drug-induced apoptosis was measured by flow cytometry.ResultsWe found that miR-200b-3p was significantly downregulated, whereas c-Myc and PRDX2 were upregulated in metastatic CRC cells and CRC tissues compared to their counterparts. An inverse correlation existed between c-Myc and miR-200b-3p, and between miR-200b-3p and PRDX2. We also found that PRDX2 was a target of miR-200b-3p. Importantly, overexpression of nontargetable PRDX2 eliminated the suppressive effects of miR-200b-3p on proliferation, invasion, EMT, chemotherapeutic resistance and metastasis of CRC cells. Moreover, c-Myc bound to the promoter of miR-200b-3p and repressed its transcription. In turn, miR-200b-3p disrupted the stability of c-Myc protein by inducing c-Myc protein threonine 58 (T58) phosphorylation and serine 62 (S62) dephosphorylation via AKT2/GSK3β pathway.ConclusionsOur findings reveal that the c-Myc/miR-200b/PRDX2 loop regulates CRC progression and its disruption enhances tumor metastasis and chemotherapeutic resistance in CRC.Electronic supplementary materialThe online version of this article (10.1186/s12967-017-1357-7) contains supplementary material, which is available to authorized users.

Hypoxia microenvironment, as a major feature of solid tumors, increases tumors progression and metastasis. To research whether hypoxia influences the epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) of gastric cancer cells and their cell biological behaviors. Human gastric cancer cell lines BGC823 and SGC7901 were cultivated in different oxygen tensions for proliferation, colony formation, soft agar formation, migration, and invasion analyses. Markers of EMT (E-cadherin, N-cadherin, Vimentin, and Snail) and markers of CSCs (Sox2, Oct4, and Bmi1) were investigated by real-time polymerase chain reaction, Western blotting, and immunofluorescent analysis. Cultivated at hypoxic condition, BGC823 and SGC7901 cells morphology began to change significantly. The cells pretreated under hypoxia grew faster than those cells always cultivated in normoxia. Meanwhile, hypoxia pretreatment dramatically promoted cell proliferation, migration and invasion, and increased capability of colony and soft agar colony formation. Furthermore, under hypoxia, E-cadherin decreased and N-cadherin, Vimentin, Snail, Sox2, Oct4, and Bmi1 increased both on the level of messenger RNA and protein. We drew a conclusion that the hypoxic microenvironment induced EMT, upgraded stem-like properties of gastric cancer cells, promoted invasion and metastasis, and behaved more malignantly.

Sestrin 2 is a conserved antioxidant protein that is involved in p53‑dependent antioxidant defenses and protects cells against oxidative stresses. The present study was conducted to examine the expression of sestrin 2 in colorectal cancer (CRC) and investigate a possible relationship between sestrin 2 expression and prognosis in CRC. The expression of sestrin 2 in human CRC tissues and cell lines was evaluated by immunohistochemical or immunofluorescent staining and western blot analysis. The correlations between sestrin 2 expression in human CRC tissues and clinicopathological variables, including overall survival (OS) and disease‑free survival (DFS), were analyzed. Both human CRC tissues and cell lines showed a decreased expression of sestrin 2. Furthermore, a low expression of sestrin 2 was significantly correlated with advanced tumor stage, lymphatic invasion, lymph node metastasis, vascular invasion and liver metastasis. Survival analysis showed that patients with low sestrin 2 staining had a significantly worse DFS and OS. Additionally, early or advanced stage CRC patients with a low expression of sestrin 2 had a shorter survival. In univariate analysis, the patients with low sestrin 2 expression, advanced tumor stage, lymphatic invasion, lymphatic node metastasis, vascular invasion, liver metastasis and peritoneal metastasis had shorter OS and DFS. In multivariate analysis, only low sestrin 2 expression, advanced tumor stage, lymphatic node metastasis, vascular invasion and liver metastasis remained as independent prognostic factors of poor OS and DFS. The findings suggested that a decreased expression of sestrin 2 is associated with an unfavorable prognosis, which suggests that it is a novel and crucial predictor for CRC metastasis.

Although, 5-Fluorouracil (5-FU) remains widely used in adjuvant therapy in patients with colon cancer, resistance to 5-FU-based chemotherapy is an important reason for treatment failure. Recent studies have reported that an enhanced reactive oxygen species (ROS) scavenging system shows drug resistance to 5-FU. Peroxiredoxin-2 (PRDX2), is an important member of the ROS scavenging system, and may be a potential target that promotes chemosensitivity to 5-FU in colon cancer. Here, we depleted PRDX2 by PRDX2-shRNA-LV transduction in two colon cancer cell lines and found that in vitro PRDX2 knockdown facilitates cell death, and apoptosis in 5-FU-treated colon cancer cells. In addition, we found that PRDX2 depletion in mice treated with 5-FU resulted in, inhibition of tumor growth, compared with mice treated with 5-FU alone. Our data also suggested that the PI3K/AKT signaling pathway links PRDX2 with 5-FU-induced apoptosis in colon cancer. Furthermore, when PRDX2 was overexpressed in colon cancer cells, we found increased p-AKT protein expression and reduced Bcl-2/Bax protein expression. PRDX2 and p-AKT protein expression were analyzed by immunohistochemistry technology in human colon carcinoma tissues. Pearson correlation coefficient is 0.873 and P<0.05. PRDX2 depletion led to reduced p-AKT expression and PI3K/AKT pathway inhibition promoted cell apoptosis in HT29 cell line. Taken together, our study suggests that decreasing the expression of PRDX2 could be a promising strategy for increasing the sensitivity of colon cancer cells to 5-FU.