Prognostic value of the advanced lung cancer inflammation index in patients with gastric cancer after radical gastrectomy: a propensity-score matching cohort study and meta-analysis.

BACKGROUND: Insufficient evidence existed about the prognostic role of the advanced lung cancer inflammation index (ALI) for gastric cancer patients who underwent curative resection. The aim of this study was to identify the predictive ability of ALI for survival after curative gastrectomy. METHODS: We retrospectively analyzed 328 gastric cancer patients who received curative gastrectomy from the database of Chongqing University Cancer Hospital, and investigated the prognostic role of the preoperative ALI compared with clinicopathological variables and other serum biomarkers, such as preoperative neutrophil-to-lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and Lymphocyte-monocyte ratio (LMR). To minimize intergroup differences, propensity score matching (PSM) analysis was employed. Additionally, we performed a meta-analysis of four cohort studies published up to October 2023 following the PRISMA guidelines. RESULTS: In the overall cohort, patients in the low ALI group had a significantly worse overall survival compared to those in the high ALI group (P < 0.0001). Subgroup analysis identified that ALI maintained its prognostic significance across different subgroups. In addition, ROC analysis showed that ALI had a higher AUC value for 3-year overall survival compared to NLR, PLR, and LMR (0.576 vs. 0.573 vs. 0.557 vs. 0.557). Multivariate analysis indicated that ALI, other than other serum biomarkers, was an independent risk factor for decreased overall survival in GC patients following curative surgery (HR = 1.449; 95%CI: 1.028-2.045; P = 0.034). Consistently, PSM analysis supported all of these findings. The meta-analysis including 4 studies evaluating 2542 patients, confirmed the association between the low ALI and poor survival outcomes. CONCLUSION: The preoperative ALI was an independent prognostic factor for survival in gastric cancer patients who underwent curative gastrectomy.

Inhibition of phospholipaseD2 increases hypoxia-induced human colon cancer cell apoptosis through inactivating of the PI3K/AKT signaling pathway.

Hypoxia is a common feature of solid tumor, and is a direct stress that triggers apoptosis in many human cell types. As one of solid cancer, hypoxia exists in the whole course of colon cancer occurrence and progression. Our previous studies shown that hypoxia induce high expression of phospholipase D2 (PLD2) and survivin in colon cancer cells. However, the correlation between PLD2 and survivin in hypoxic colon cancer cells remains unknown. In this study, we observed significantly elevated PLD2 and survivin expression levels in colon cancer tissues and cells. This is a positive correlation between of them, and co-expression of PLD2 and survivin has a positive correlation with the clinicpatholic features including tumor size, TNM stage, and lymph node metastasis. We also found that hypoxia induced the activity of PLD increased significant mainly caused by PLD2 in colon cancer cells. However, inhibition the activity of PLD2 induced by hypoxia promotes the apoptosis of human colon cancer cells, as well as decreased the expression of apoptosis markers including survivin and bcl2. Moreover, the pharmacological inhibition of PI3K/AKT supported the hypothesis that promotes the apoptosis of hypoxic colon cancer cells by PLD2 activity inhibition may through inactivation of the PI3K/AKT signaling pathway. Furthermore, interference the PLD2 gene expression leaded to the apoptosis of hypoxic colon cancer cells increased and also decreased the expression level of survivin and bcl2 may through inactivation of PI3K/AKT signaling pathway. These results indicated that PLD2 play antiapoptotic role in colon cancer under hypoxic conditions, inhibition of the activity, or interference of PLD2 gene expression will benefit for the treatment of colon cancer patients.

Clinical significance of the advanced lung cancer inflammation index in gastrointestinal cancer patients: a systematic review and meta-analysis.

Background: The advanced lung cancer inflammation index (ALI) has been identified as a scientific and clinical priority in multiple malignancies. The aim of this study is to investigate the value of the ALI before treatment in evaluating postoperative complications (POCs) and survival outcomes in patients with gastrointestinal (GI) cancer. Methods: Electronic databases including PubMed, Embase and Web of Science were comprehensively reviewed up to June 2022. The endpoints were POCs and survival outcomes. Subgroup analyses and sensitivity analyses were also performed. Results: Eleven studies including 4417 participants were included. A significant heterogeneity in the ALI cut-off value among studies was observed. Patients in the low ALI group showed increased incidence of POCs (OR=2.02; 95%CI:1.60-2.57; P<0.001; I2 = 0%). In addition, a low ALI was also significantly associated with worse overall survival (HR=1.96; 95%CI: 1.58-2.43; P<0.001; I2 = 64%), which remained consistent in all subgroups based on country, sample size, tumor site, tumor stage, selection method and Newcastle Ottawa Scale score. Moreover, patients in the low ALI group had an obviously decreased disease-free survival compared to these in the high ALI group (HR=1.47; 95%CI: 1.28-1.68; P<0.001; I2 = 0%). Conclusion: Based on existing evidence, the ALI could act as a valuable predictor of POCs and long-term outcomes in patients with GI cancer. However, the heterogeneity in the ALI cut-off value among studies should be considered when interpreting these findings.

Risk Analysis of Positive PD-L1 Expression and Clinicopathological Features and Survival Prognosis in Patients with Colorectal Cancer: Systematic Review and Meta-Analysis.

In order to explore the significance of PD-L1 expression in the prognosis and clinicopathological characteristics of colorectal cancer (CRC), the PubMed, Embase, Web of Science, Cochrane Library, CNKI, and multisquare databases are systematically searched for the relevant relationship between PD-L1 expression and CRC prognosis. The search time is completed until June 2021. Literature is filtered and data extracted by inclusion exclusion criteria, and Meta-analysis is performed with Stata SE12.0 software. 16 documents are included, and a total of 1997 CRC patients are included. The results show that recurrence-free survival (RFS) [OR = 2.69, 95%CI (2.07,3.48), P < 0.00001, I2 = 0%, Z = 7.50), and disease-free survival (DFS) (OR = 3.71, 95% CI (2.32,5.93), P < 0.00001, I2 = 37%, Z = 5.48) and PD-L1 expression and tumor differentiation (OR = 4.00, 95%CI (2.97,5.38), P < 0.00001, I2 = 0%, Z = 9.11) and lymphatic action metastasis (OR = 2.69,95% CI (2.07,3.48), P < 0.00001, I2 = 0%, Z = 7.50) is significantly associated.PD-L1 expression in tumor tissue suggests a poor prognosis in colorectal cancer, and the predictive significance of PD-L1 expression and PD-L1 expression in tumor cells in tumor-infiltrating immune cells may be inconsistent.

Laparoscopic radical resection for situs inversus totalis with colonic splenic flexure carcinoma: A case report.

BACKGROUND: Situs inversus totalis (SIT) is a rare group of congenital developmental malformations in the clinical setting, with all organs in the chest and abdomen existing in a mirror image reversal of their normal positions. Few reports have described laparoscopic surgery for colorectal cancer in patients with SIT, and it is considered difficult even for an experienced surgeon because of the mirror positioning. We present a case report of laparoscopic radical resection of a colonic splenic flexure carcinoma in a patient with SIT. CASE SUMMARY: A 72-year-old male was referred to our hospital with colonic splenic flexure carcinoma, and computed tomography showed that all the organs in the chest and abdomen were inverted. Laparoscopic hemicolectomy with complete mesocolic excision was safely performed. The operating surgeon stood on the patient's left side, which is opposite of the normal location. CONCLUSION: Abdominal computed tomography is an effective method for diagnosing SIT preoperatively in patients with colonic splenic flexure carcinomas. Laparoscopic radical resection is difficult, but it is well established and safe. The surgeon should stand in the opposite position and perform backhand operations.

Elemene-containing hyperthermic intraperitoneal chemotherapy combined with chemotherapy for elderly patients with peritoneal metastatic advanced gastric cancer.

BACKGROUND: Almost all elderly patients with peritoneal metastatic gastric cancer (PGC) are unlikely to tolerate cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and adjuvant chemotherapy. However, determining how to optimize the treatment strategy for such patients has always been a clinical problem. Both HIPEC and palliative adjuvant chemotherapy can benefit patients with PGC. Therefore, optimizing HIPEC and chemotherapy regimens has potential clinical value in reducing side effects, and improving treatment tolerance and clinical effectiveness. AIM: To explore the effect of HIPEC containing elemene, which is an anti-cancer component extracted in traditional Chinese herbal medicine, combined with reduced capecitabine and oxaliplatin (CapeOx) chemotherapy regimens, in elderly patients with PGC. METHODS: In the present study, 39 of 52 elderly PGC patients were included and assigned to different HIPEC treatment groups [lobaplatin group (group L) and mixed group (group M)] for analysis. Lobaplatin was used for all three HIPECs in group L. In group M, lobaplatin was used in the middle of the three HIPECs, and elemene was used for the first and third HIPEC. After HIPEC, patients received CapeOx chemotherapy. The incidence of complications (abdominal infection, lung infection, and urinary tract infection), myelosuppression, immune function (CD4/CD8 ratio), average length of hospital stay, and prognosis were compared between these two groups. RESULTS: There was no significant difference in the incidence of complications between the two groups during hospitalization (P > 0.05). Compared to patients in group M, patients in group L exhibited severe myelosuppression (P = 0.027) and increased length of hospital stay (P = 0.045). However, no overall survival benefit was observed in group M. Furthermore, the immune function of patients in group M was less affected (P < 0.001), when compared to that of patients in group L. The multivariate analysis suggested that the cycles of chemotherapy after perfusion significantly affected the prognosis of patients in both groups. CONCLUSION: Compared to the lobaplatin-based HIPEC regimen, the administration of elemene reduced the myelosuppression incidence in elderly PGC patients. The present study sheds light on the implementation of this therapeutic strategy for this set of patients.

RGS1 serves as an antitumor target to inhibit proliferation of NICN87-DR cells and tumor growth in the gastric cancer mouse model.

Gastric cancer is becoming the 4th leading cause of cancer-associated death worldwide. The purpose of this study was to investigate the role of RGS1 in gastric cancer in vitro and in vivo. Proliferation, migration, invasion, and colony formation of NCIN87 cells and drug-resistant NCIN87 cells (NCIN87-DR) were determined. Cell apoptosis and cell cycle were examined using a flow cytometry assay. RGS1 gene knock-down vector (pLVshshRGS1) and Xenograft tumor mouse model was generated. RGS1 and epithelial-mesenchymal transition (EMT) associated markers, including E-cadherin (E-cad), N-cadherin (N-cad), Slug, and Vimentin were detected using a western blotting assay. Tumor size of Xenograft tumor mouse was measured and Ki67 expression was detected using the immunohistochemical assay. NCIN87-DR cells demonstrated significantly lower proliferation, migration, and invasion compared to those of NCIN87 cells (p < 0.05). NCIN87-DR cells showed obvious early apoptosis and displayed obvious alterations for the cell cycle. NCIN87-DR cells exhibited predominantly higher RGS1 expression than that in NCIN87 cells (p < 0.01). E-cad expression was markedly decreased (p < 0.01) and N-cad (p < 0.05), Slug (p < 0.01), Vimentin (p < 0.05) expressions were significantly increased in NCIN87-DR cells than those in NCIN87 cells. RGS1 gene silence remarkably reduced NCIN87-DR proliferation compared to that in NCIN87-DR cells without treatment (p < 0.01). RGS1 gene-silenced NCIN87-DR cell immunization predominantly inhibited tumor growth in Xenograft tumor mouse than that without RGS1 silence (p < 0.05). RGS1 gene-silenced NCIN87-DR cell immunization significantly downregulated Ki67 expression in tumor tissues compared with that without RGS1 silence. In conclusion, RGS1 gene silence reduced the proliferation of NCIN87-DR cells in vitro and inhibited tumor growth in vivo. Therefore, RGS1 served as an antitumor target for the gastric cancer treatment.

Detection of asymptomatic recurrence following curative surgery improves survival in patients with gastric cancer: A systematic review and meta-analysis.

Background: To date, there is no evidence that intensive follow-up provides survival benefit in gastric cancer patients undergoing curative gastrectomy. The aim of this study is to investigate the efficacy of detection of asymptomatic recurrence using intensive surveillance strategy in long-term survival after curative gastric cancer surgery. Methods: A systematic review of electronic databases including PubMed, Embase, Web of Science, the Cochrane Library and China National Knowledge Infrastructure, Clinical Trials Registry and Google Scholar was performed up to April 2022. The primary outcomes were survival outcomes: overall survival, recurrence-free survival and post-recurrence survival. The secondary endpoints were clinicopathological features, recurrence patterns and treatment after recurrence. The registration number of this protocol is PROSPERO CRD42022327370. Results: A total of 11 studies including 1898 participants were included. In the pooled analysis, the detection of asymptomatic recurrence was significantly associated with an improved overall survival compared to patients showing symptoms of recurrence (HR=0.67; 95%CI: 0.57-0.79; P<0.001), which was primarily driven by the prolongation of post-recurrence survival (HR=0.51; 95%CI: 0.42-0.61; P<0.001), since there was no significant difference observed in recurrence-free survival (HR=1.12; 95%CI: 0.81-1.55; P=0.48) between the two groups. Meanwhile, male sex and advanced T stage were more frequently observed in the symptomatic recurrence group. Furthermore, patients in the symptomatic recurrence group had a higher proportion of peritoneal relapse but lower proportion of distant lymph node metastasis. Additionally, patients in the symptomatic recurrence group were less likely to receive surgery treatment and post-recurrence chemotherapy. Conclusion: The detection of asymptomatic recurrence using intensive follow-up was associated with an appreciable improvement in overall survival. However, more robust data from high-quality studies are still required to verify this issue. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=327370, identifier CRD42022327370.

Comparison of radiofrequency ablation and surgical resection for hepatocellular carcinoma conforming to the Milan criteria: a meta-analysis.

BACKGROUND: The purpose of this study was to include all current randomized controlled trials to compare the clinical efficacy between radiofrequency ablation (RFA) and surgical resection (SR) in patients with hepatocellular carcinoma who meet the Milan criteria using meta-analysis techniques. METHODS: We conducted literature search of PubMed, Embase and Cochrane library clinical database for studies of RFA versus SR. Only randomized clinical trials were included. The odds ratios (OR) were pooled and calculated with 95% confidence intervals (CIs) for both fixed-effects and random-effects models. RESULTS: A total of 8 randomized controlled trials with 1177 patients were included in the present meta-analysis. There were no significantly difference between the patients underwent SR or RFA in terms of 1, 3 and 5 years' overall survival rate (OR 0.87, 95% CI 0.46-1.64; OR 0.84, 95% CI 0.57-1.24 and OR 1.03, 95% CI 0.61-1.73, respectively). And there were no significantly difference between the patients received SR and RFA in terms of 1 and 3 years' disease-free survival rate (OR 0.85, 95% CI 0.61-1.18 and OR 0.77, 95% CI 0.57-1.03). However, it is worth noting that RFA has advantages over SR in terms of treatment-related complications (OR 0.65, 95% CI 0.44-0.80; P < 0.05), post-operative mortality, length of stay and hospitalization costs. CONCLUSION: For patients with hepatocellular carcinoma who meet the Milan criteria, RFA exhibited similar clinical efficacy to SR.

Prdx2 Upregulation Promotes the Growth and Survival of Gastric Cancer Cells.

Peroxiredoxins (Prdxs) play important roles in cell proliferation, differentiation, and the mediation of intracellular signalling pathways. Prdx2 is an important member of the peroxiredoxin family and is upregulated in many cancers. Until now, the biological functions of Prdx2 in gastric cancer have not been completely understood, and the underlying mechanisms remain elusive. The aim of this study was to identify the role of Prdx2 on the growth of gastric cancer cells and the underlying mechanisms. We demonstrated that Prdx2 was highly expressed in gastric cancer tissues and cell lines and that the over-expression of Prdx2 correlated with the progression of gastric cancer. Further, Prdx2 was silenced with a specific, lentiviral vector-mediated shRNA, and this suppressed the proliferation of gastric cancer cells and promoted the apoptosis of gastric cancer cells. Finally, the knockdown of Prdx2 contributed to the attenuated gastric cancer growth in BALB/c nude mice. In conclusion, these findings demonstrate that Prdx2 may participate in the carcinogenesis and development of gastric cancer.

Knockdown of PRDX2 sensitizes colon cancer cells to 5-FU by suppressing the PI3K/AKT signaling pathway.

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.

Sestrin 2 suppresses cells proliferation through AMPK/mTORC1 pathway activation in colorectal cancer.

Sestrin 2 is a conserved antioxidant protein that reduces reactive oxygen species (ROS) and inhibits mammalian target of rapamycin complex 1 (mTORC1). We previously showed that sestrin 2 is abnormally decreased in colorectal cancer (CRC). To elucidate the molecular mechanism behind the potential contribution of sestrin 2 to CRC, we used a lentiviral expression vector system to determine the effects of sestrin 2 overexpression on human CRC cells. We found that sestrin 2 overexpression decreased ROS production, inhibited cell growth, and stimulated apoptosis in two CRC cell lines. In parallel, expression of the proliferation marker PCNA was decreased, proapoptotic caspase 3, 7, and 9 levels were increased, and expression of the anti-apoptotic protein survivin was reduced. Sestrin 2 overexpression also activated the adenosine monophosphate-activated protein kinase (AMPK) pathway, and suppressed mTORC1 signaling. Treating CRC cells with compound C, an AMPK inhibitor, reversed or attenuated changes in proliferation, apoptosis, and signaling proteins of the AMPK/mTORC1 axis. In a xenograft mouse model, CRC growth was attenuated by sestrin 2 overexpression. These results suggest that sestrin 2 suppresses CRC cell growth through activation of the AMPK/mTORC1 pathway and induction of apoptosis, and could be a novel pharmacological target for the treatment of CRC.

An integrated lncRNA, microRNA and mRNA signature to improve prognosis prediction of colorectal cancer.

Although the outcome of patients with colorectal cancer (CRC) has improved significantly, prognosis evaluation still presents challenges due to the disease heterogeneity. Increasing evidences revealed the close correlation between aberrant expression of certain RNAs and the prognosis. We envisioned that combined multiple types of RNAs into a single classifier could improve postoperative risk classification and add prognostic value to the current stage system. Firstly, differentially expressed RNAs including mRNAs, miRNAs and lncRNAs were identified by two different algorithms. Then survival and LASSO analysis was conducted to screen survival-related DERs and build a multi-RNA-based classifier for CRC patient stratification. The prognostic value of the classifier was self-validated in the TCGA CRC cohort and further validated in an external independent set. Finally, survival receiver operating characteristic analysis was used to assess the performance of prognostic prediction. We found that the multi-RNA-based classifier consisted by 12 mRNAs, 1miRNA and 1 lncRNA, which could divide the patients into high and low risk groups with significantly different overall survival (training set: HR 2.54, 95%CI 1.67-3.87, p<0.0001; internal testing set: HR 2.54, 95%CI 1.67-3.87, p<0.0001; validation set: HR 5.02, 95% CI 2.2-11.6; p=0·0002). In addition, the classifier is not only independent of clinical features but also with a similar prognostic ability to the well-established TNM stage (AUC of ROC 0.83 versus 0.74, 95% CI = 0.608-0.824, P =0.0878). Furthermore, combination of the multi-RNA-based classifier with clinical features was a more powerful predictor of prognosis than either of the two parameters alone. In conclusion, the multi-RNA-based classifier may have important clinical implications in the selection of patients with CRC who are at high risk of mortality and add prognostic value to the current stage system.

Fbxw7 regulates tumor apoptosis, growth arrest and the epithelial-to-mesenchymal transition in part through the RhoA signaling pathway in gastric cancer.

F-box and WD repeat domain-containing7 (Fbxw7), a member of the F-box family of proteins, which are components of an E3 ubiquitin ligase complex, plays an important role as a general tumor suppressor in regulating the effects of various oncoproteins. Recently, accumulating studies have shown that Fbxw7 plays an important role in tumor cell motility, invasion and cancer metastasis. However, little is known about the signaling mechanisms that regulate tumor apoptosis, growth arrest and the epithelial-to-mesenchymal transition (EMT) in gastric cancer. In our study, we confirmed that Fbxw7 expression was decreased in gastric cancer tissues, and that Fbxw7 inhibited gastric cancer progression by inducing apoptosis and growth arrest. Furthermore, gastric cancer migration and invasion were decreased or increased following Fbxw7 overexpression or knockdown, respectively, and the expressions of various EMT markers, such as E-cadherin, N-cadherin and vimentin, were altered after Fbxw7 inhibition or overexpression. Furthermore, we demonstrated that Fbxw7 inhibits the EMT via the down-regulation of Snail 1 and ZEB 1, which are upstream transcription factors that promote this process. Additionally, RhoA showed higher expression in the same gastric cancer tissues than in normal tumor-adjacent samples. We found that Fbxw7 expression was negatively correlated with RhoA protein expression in gastric cancer tissues based on Pearson's correlation coefficient analysis. Moreover, we found that RhoA protein abundance was regulated by Fbxw7 via ubiquitination and proteasomal degradation in gastric cancer. We further demonstrated the effects of RhoA re-expression or inhibition on stable Fbxw7-overexpressing or Fbxw7-silenced cell lines in vitro and in vivo. These results suggest that Fbxw7 induces apoptosis and growth arrest and inhibits the EMT in part by down-regulating the RhoA signaling pathway.

Peroxiredoxin 2 is essential for maintaining cancer stem cell-like phenotype through activation of Hedgehog signaling pathway in colon cancer.

Cancer stem cells (CSCs) are a key target for reducing tumor growth, metastasis, and recurrence. Redox status is a critical factor in the maintenance of CSCs, and the antioxidant enzyme Peroxiredoxin 2 (Prdx2) plays an important role in the development of colon cancer. Therefore, we investigated the contribution of Prdx2 to the maintenance of stemness of colon CSCs. Here, we used short-hairpin RNAs and a Prdx2-overexpression vector to determine the effects of Prdx2. We demonstrated that knockdown of Prdx2 reduced the self-renewal and sphere formation and resulted in increased 5-FU-induced apoptosis in human colon CSCs. Prdx2 overexpression induced reversion of the self-renewal and sphere formation. Furthermore, the effects of Prdx2 resulted in an altered expression of stemness associated with the Hh/Gli1 signaling pathway. Finally, knockdown of Prdx2 in CD133+ cells reduced the volume of xenograft tumors in BALB/c-nu mice. Taken together, colon CSCs overexpress Prdx2, which promotes their stem cell properties via the Hh/Gli1 signaling pathway. The results suggest that Prdx2 may be an effective therapeutic target for the elimination of CSCs in colorectal cancer.

Hypoxia-inducible factor 1-alpha up-regulates the expression of phospholipase D2 in colon cancer cells under hypoxic conditions.

Hypoxia is a common characteristic of solid tumors. Recent studies confirmed that phospholipase D2 (PLD2) plays significant roles in cancer progression. In this study, correlation between the expression of PLD2 and the change in the protein level of hypoxia-inducible factor 1-alpha (HIF1-α) was studied. Thirty human colon cancer tissues were examined for the expression of HIF1-α and PLD2 protein, and mRNA levels. SW480 and SW620 cells were exposed to normoxia (20 %) or hypoxia (<1 %). HIF1-α and PLD2 protein, and mRNA levels were analyzed by Western blot and qRT-PCR, respectively. Growth studies were conducted on cells with HIF1-α inhibition through xenograft tumor model. Finally, PLD2 protein was detected by Western blot analysis in vivo. There was a positive correlation between HIF1-α and PLD2 in colon cancer tissues. Hypoxic stress induced PLD2 mRNA and protein expression in SW480 and SW620 cells. Cells transfected with HIF1-α siRNA showed attenuation of hypoxia stress-induced PLD2 expression. In vivo growth decreased in response to HIF1-α and PLD2 inhibition. These results suggest that PLD2 expression in colon cancer cells is up-regulated via HIF1-α in response to hypoxic stress and underscores the crucial role of HIF1-α-induced PLD2 in tumor growth.

Peroxiredoxin 2 is involved in vasculogenic mimicry formation by targeting VEGFR2 activation in colorectal cancer.

The mammalian peroxiredoxin 2 (Prdx2) is a member of thiol-dependent antioxidant proteins and plays an important role in the progression of colorectal cancer (CRC). The aim of this study was to confirm the role of Prdx2 in formation of VM and progression of CRC. Immunohistochemistry and CD34/periodic acid Schiff double staining were performed to explore the expression of Prdx2 and VM formation in 70 CRC tissues, and there was a positive correlation between Prdx2 expression and VM formation by the Pearson correlation coefficient (r = 0.282, p < 0.05). Prdx2 was suppressed in poorly differentiated HCT116 cells by Prdx2-siRNA-LV transduction. The expression of Prdx2 at both mRNA and protein levels in HCT116 cells transfected with the Prdx2 siRNA was significantly lower than that of negative control siRNA as confirmed by quantitative real-time PCR and Western blotting analysis, respectively (p < 0.05). The well-established in vitro 3D culture model was chosen to investigate the VM formation of HCT116 cells. The numbers of the tubular structures were significantly fewer in Prdx2 siRNA explants than those of negative control siRNA explants after VEGF induction (p < 0.05). Although VEGFR2 expressions had no change after VEGF induction, we found that VEGFR2 phosphorylation levels were markedly reduced in cells of siPrdx2 over time compared with those of negative control siRNA by Western blotting analysis (p < 0.05, p < 0.01). The effects of Prdx2 siRNA on the invasive capabilities of HCT116 cells with VEGF induction were examined by using Matrigel invasion chamber assay. The invasive capabilities of HCT116 cells were significantly declined in Prdx2 siRNA explants than those of negative control siRNA explants (p < 0.05). The effects of Prdx2 siRNA on pathological tumor growth were examined by using a tumor xenograft model in vivo. After implant of HCT116 cells that transduced with Prdx2 siRNA and negative control siRNA as xenografts into nude mice, the growth of xenograft tumors with Prdx2 siRNA was much slower than that of negative control siRNA, and the volumes of tumor xenografts with Prdx2 siRNA were smaller than those of negative control siRNA after 5 weeks (p < 0.05). Further conclusion showed that Prdx2 regulates VM formation by targeting VEGFR2 activation, which now represents as a therapeutic target for RC.

PRRX1 promotes epithelial-mesenchymal transition through the Wnt/ß-catenin pathway in gastric cancer.

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 ß-catenin and the Wnt/ß-catenin target c-Myc. Furthermore, the inhibition of the Wnt/ß-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/ß-catenin signaling and that PRRX1 upregulation is closely correlated with gastric cancer metastasis.

VGLL4 inhibits EMT in part through suppressing Wnt/ß-catenin signaling pathway in gastric cancer.

VGLL4 is a member of the Vestigial-like proteins that functions as a tumor suppressor, which directly competes with YAP for binding TEADs in several cancer types. Recently, an increasing number of studies have reported that VGLL4 acts as a crucial role in regulating cell mobility, migration, and invasion. However, little is known about the signaling mechanisms in regulating epithelial-mesenchymal transition (EMT) of gastric cancer. In our study, we confirmed that the expression level of VGLL4 was down-regulated in gastric cancer tissues, and reduced VGLL4 expression levels inhibited apoptosis and promoted proliferation, migration, and invasion. Additionally, we found a phenomenon that VGLL4 was associated with the change in nuclear location of ß-catenin, which suggested that ß-catenin was a significant downstream factor of VGLL4. These results suggest that VGLL4 suppressed EMT in part via negative regulation of Wnt/ß-catenin signaling pathway. Taken together, our study demonstrated that VGLL4 is important in the process of suppressing tumor progression of gastric cancer and provided a potential therapeutic strategy for gastric cancer.

Overexpression of peroxiredoxin 2 inhibits TGF-ß1-induced epithelial-mesenchymal transition and cell migration in colorectal cancer.

Although human peroxiredoxin 2 (PRDX2) has been implicated in tumor progression (e.g., invasion and metastasis), little is known regarding its role in the epithelial­mesenchymal transition (EMT) process during tumorigenesis. The present study offers the first evidence, to the best of our knowledge, that the antioxidant enzyme PRDX2 has an important role in regulating the EMT process. It was demonstrated that overexpression of PRDX2 leads to changes in cell morphology in vitro and potent inhibition of the transforming growth factor (TGF)­ß1­induced EMT and cell migration of colorectal cancer (CRC) cells. Furthermore, PRDX2 regulates the expression of EMT markers, EMT­related transcription factors and metastasis­related factors in CRC cells. These results provide new insight into the role of PRDX2 in regulating EMT, cell migration and metastasis of CRC cells. It was concluded that the upregulation of PRDX2 may be correlated with EMT and contributes to the pathogenesis of CRC by inhibiting EMT, cell migration and metastasis. Taken together, these findings suggest that PRDX2 may be a key regulator of invasion and metastasis by inhibiting EMT of CRC cells, and also identifies a therapeutic strategy to effectively decrease the lethality of highly malignant types of CRC.