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.

Effect of perioperative blood transfusion on complications and prognosis after radical gastrectomy in elderly patients: a retrospective study of 1,666 cases.

Background: Multiple studies have examined the effect of perioperative blood transfusion (BTF) on postoperative complications and the prognosis of gastric cancer patients, but the conclusions remain controversial, and few studies related to elderly patients are present. This study sought to examine the effect of perioperative BTF on postoperative complications and the prognosis of elderly patients who underwent radical gastrectomy. Methods: The clinical data of 1,666 elderly patients (aged ≥60 years) at Xijing Hospital from October 2013 to October 2021 were retrospectively analyzed. The patients were stratified into the perioperative BTF group and the perioperative non-BTF group. The clinicopathological characteristics, postoperative complications, and long-term prognoses of the patients were compared. Results: There were significant differences in terms of sex, tumor location, tumor size, gastrectomy range, tumor differentiation, T stage, N stage, tumor-node-metastasis (TNM) stage, preoperative anemia, and intraoperative blood loss between the two groups (P<0.05). The incidence of postoperative fever in the BTF group was significantly higher than that in the non-BTF group (31.6% vs. 15.4%, P<0.001), but there were no significant differences in the other complications between the two groups (P>0.05). The survival analysis showed that in stage III patients, the prognosis of the BTF group was inferior to that of the non-BTF group [the 3-year overall survival (OS) rates of the groups were 33.7% vs. 47.9% respectively, P<0.001], while there was no significant difference between the two groups among the stage I and stage II patients (P>0.05). There was no significant difference in the prognosis of patients with different transfusion times (preoperative/intraoperative/postoperative) (P>0.05). The multivariate analysis indicated that perioperative BTF was not an independent risk factor for prognosis in elderly patients with gastric cancer overall or elderly patients with gastric cancer in stage III (P>0.05). Conclusions: Perioperative BTF may elevate the incidence of fever but has no significant effect on other complications in elderly patients after radical gastrectomy. Perioperative BTF is not an independent risk factor affecting the postoperative prognosis of elderly patients with gastric cancer.

Prognostic value of dynamic changes of pre- and post-operative tumor markers in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) prognosis assessment is vital for personalized treatment plans. This study investigates the prognostic value of dynamic changes of tumor markers CEA, CA19-9, CA125, and AFP before and after surgery and constructs prediction models based on these indicators. METHODS: A retrospective clinical study of 2599 CRC patients who underwent radical surgery was conducted. Patients were randomly divided into training (70%) and validation (30%) datasets. Univariate and multivariate Cox regression analyses identified independent prognostic factors, and nomograms were constructed. RESULTS: A total of 2599 CRC patients were included in the study. Patients were divided into training (70%, n = 1819) and validation (30%, n = 780) sets. Univariate and multivariate Cox regression analyses identified age, total number of resected lymph nodes, T stage, N stage, the preoperative and postoperative changes in the levels of CEA, CA19-9, and CA125 as independent prognostic factors. When their postoperative levels are normal, patients with elevated preoperative levels have significantly worse overall survival. However, when the postoperative levels of CEA/CA19-9/CA125 are elevated, whether their preoperative levels are elevated or not has no significance for prognosis. Two nomogram models were developed, and Model I, which included CEA, CA19-9, and CA125 groups, demonstrated the best performance in both training and validation sets. CONCLUSION: This study highlights the significant predictive value of dynamic changes in tumor markers CEA, CA19-9, and CA125 before and after CRC surgery. Incorporating these markers into a nomogram prediction model improves prognostic accuracy, enabling clinicians to better assess patients' conditions and develop personalized treatment plans.

Activation of RhoA/ROCK2 signaling by hypoxia-inducible factor 1α in promoting tumor growth and metastasis in human colon cancer.

Background: Recent evidence strongly suggests the profound role of the tumor microenvironment in cancer development and progression. A hypoxic microenvironment is widely acknowledged to be a typical feature of solid tumors, and altered hypoxia-inducible factor 1α (HIF-1α) expression has been associated with the formation and the progression of many solid tumors; however, the underlying mechanism of this relationship remains obscure. Methods: Clinical colorectal cancer tissue samples were collected to detect the differential expression of HIF-1α, Ras homolog family member A (RhoA), and Rho-associated, coiled-coil containing protein kinase 2 (ROCK2). With hypoxic stress, small interfering RNA (siRNA) targeting HIF-1α, lentivirus transfection of RhoA was used to study the mechanism of HIF-1α and RhoA/ROCK2 signaling pathways in the growth and metastasis of colon cancer. Results: According to Cell Counting Kit 8, wound-healing, and Transwell assays, HIF-1α expression activated the RhoA/ROCK2 pathway within colon cancer cell lines, accelerating their growth and expansion. In cells transfected with LV-RhoA, inactivating the RhoA/ROCK2 pathway with the specific inhibitor Y-27632 decreased tumor growth and metastasis under hypoxic conditions, while activating the RhoA/ROCK2 pathway restored these biological properties. The Western blot results showed that the expression levels of pMYPT1, cyclin D1, and MMP2 in the siRNA + LV-RhoA group were also significantly increased compared with those in the siRNA group. Conclusions: For the first time, this study demonstrated that HIF-1α can promote the growth and metastasis of colon cancer via directly affecting RhoA/ROCK2 signaling and thus represents a novel therapeutic target for colon cancer.

Small extracellular vesicles-mediated cellular interactions between tumor cells and tumor-associated macrophages: Implication for immunotherapy.

The tumor microenvironment consists of cancer cells and various stromal cells, including macrophages, which exhibit diverse phenotypes with either pro-inflammatory (M1) or anti-inflammatory (M2) effects. The interaction between cancer cells and macrophages plays a crucial role in tumor progression. Small extracellular vesicles (sEVs), which facilitate intercellular communication, are known to play a vital role in this process. This review provides a comprehensive summary of how sEVs derived from cancer cells, containing miRNAs, lncRNAs, proteins, and lipids, can influence macrophage polarization. Additionally, we discuss the impact of macrophage-secreted sEVs on tumor malignant transformation, including effects on proliferation, metastasis, angiogenesis, chemoresistance, and immune escape. Furthermore, we address the therapeutic advancements and current challenges associated with macrophage-associated sEVs, along with potential solutions.

Cuproptosis-Mediated Patterns Characterized by Distinct Tumor Microenvironment and Predicted the Immunotherapy Response for Gastric Cancer.

Cuproptosis is a newly discovered programmed cell death process, and several cuproptosis-related genes have been reported to regulate cancer cell proliferation and progression. The association between cuproptosis and tumor microenvironment in gastric cancer (GC) remains unclear. This study aimed to explore multiomics characteristics of cuproptosis-related genes regulating tumor microenvironment and provide strategies for prognosis and prediction of immunotherapy response in GC patients. We collected 1401 GC patients from the TCGA and 5 GEO data sets and identified three different cuproptosis-mediated patterns, each of which shared a distinct tumor microenvironment and different overall survival. The GC patients with high cuproptosis levels were enriched in CD8+ T cells and had a better prognosis. Whereas, the low cuproptosis level patients were associated with inhibitory immune cell infiltration and had the worst prognosis. In addition, we constructed a 3-gene (AHCYL2, ANKRD6 and FDGFRB) cuproptosis-related prognosis signature (CuPS) via Lasso-Cox and multivariate Cox regression analysis. The GC patients in the low-CuPS subgroup had higher TMB levels, MSI-H fractions, and PD-L1 expression, which suggests a better immunotherapy response. Therefore, the CuPS might have the potential value for predicting prognosis and immunotherapy sensitivity in GC patients.

Single-cell analysis unveils activation of mast cells in colorectal cancer microenvironment.

The role of mast cells (MCs) in colorectal cancer (CRC) remains unclear, and a comprehensive single-cell study on CRC MCs has not been conducted. This study used a multi-omics approach, integrating single-cell sequencing, spatial transcriptomics, and bulk tissue sequencing data to investigate the heterogeneity and impact of MCs in CRC. Five MC signature genes (TPSAB1, TPSB2, CPA3, HPGDS, and MS4A2) were identified, and their average expression was used as a marker of MCs. The MC density was found to be lower in CRC compared to normal tissue, but MCs in CRC demonstrated distinct activation features. Activated MCs were defined by high expression of receptors and MC mediators, while resting MCs had low expression. Most genes, including the five MC signature genes, were expressed at higher levels in activated MCs. The MC signature was linked to a better prognosis in both CRC and pan-cancer patient cohorts. Elevated KITLG expression was observed in fibroblasts and endothelial cells in CRC samples compared to normal tissue, and co-localization of MCs with these cell types was revealed by spatial transcriptome analysis. In conclusion, this study finds decreased MC density in CRC compared to normal tissue, but highlights a shift in MC phenotype from CMA1high resting cells to activated TPSAB1high, CPA3high, and KIThigh cells. The elevated KITLG expression in the tumor microenvironment's fibroblasts and endothelial cells may activate MCs through the KITLG-KIT axis, potentially suppressing tumor progression.

Prognostic value of normal levels of preoperative tumor markers in colorectal cancer.

Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), and alpha-fetoprotein (AFP) are widely used tumor markers for colorectal cancer (CRC), but their clinical significance is unknown when the levels of these tumor markers were within the normal range. This retrospective study included 2145 CRC patients. The entire cohort was randomly divided into training and validation datasets. The optimal cut-off values of tumor markers were calculated using X-tile software, and univariate and multivariate analyses were performed to assess its association with overall survival (OS). The nomogram model was constructed and validated. The entire cohort was randomly divided into a training dataset (1502 cases, 70%) and a validation dataset (643 cases,30%). Calculated from the training dataset, the optimal cut-off value was 2.9 ng/mL for CEA, 10.1 ng/mL for CA19-9, 13.4 U/mL for CA125, and 1.8 ng/mL for AFP, respectively. Multivariate analysis revealed that age, tumor location, T stage, N stage, preoperative CA19-9, and CA125 levels were independent prognostic predictors. Even within the normal range, CRC patients with relatively high levels of CA19-9 or CA125 worse OS compared to those with relatively low levels. Then, based on the independent prognostic predictors from multivariate analysis, two models with/without (model I/II) CA19-9 and CA125 were built, model I showed better prediction and reliability than model II. Within the normal range, relatively high levels of preoperative CA19-9 and CA125 were significantly associated with poor OS in CRC patients. The nomogram based on CA19-9 and CA125 levels showed improved predictive accuracy ability for CRC.

Expression of HIF-1α, ANXA3, CD133 and their associations with clinicopathological parameters in human colon carcinoma.

Background: Our previous study found an association between the expression of hypoxia-inducible factor-1alpha (HIF-1α) and annexin A3 (ANXA3) in colon cancer. ANXA3 correlated with expansion of CD133+ tumor cells in hepatocellular carcinoma cancer stem-like cells (CSCs), for which CD133 has been recognized as a typical marker in many cancer cells, including: gastric cancer, lung cancer and colorectal cancer. But the expression and association of HIF-1α, ANXA3 and CD133 in colon cancer has not been reported. The purpose of the present study was to evaluate the correlation among the expression of HIF-1α, ANXA3 and CD133 in human colon cancer and to investigate its clinicopathological parameters. Methods: The data for 35 patients diagnosed with colon adenocarcinoma in The First Affiliated Hospital of Chongqing Medical University and who had undergone colectomy, tumor and adjacent normal colon tissues were collected. The expressions of HIF-1α, ANXA3, and CD133 were measured by immunohistochemistry in colon cancer and surrounding non-tumor tissues and measured by using a semiquantitative score system. Finally, relationships between HIF-1α, ANXA3, and CD133 immunohistochemical staining and clinicopathologic variables were analyzed using the Fisher's exact probability test. Associations between the expression levels of HIF-1α, ANXA3, and CD133 were analyzed by the Spearman's rank correlation. Results: The positive rate of expression of HIF-1α in colon cancer and normal colon tissue was 80% (28/35) and 14% (5/35), 77% (27/35) and 20% (7/35) for ANXA3, and 71% (25/35) and 23% (8/35) for CD133, respectively. The coefficient of correlation for the association among HIF-1α, ANXA3 and CD133 showed that the expression of HIF-1α was positively related with ANXA3 and CD133 in colon cancer tissues (r1=0.408, P1=0.015, r2=0.474, P2=0.004) and a positive correlation was observed between the expression of ANXA3 and CD133 (r3=0.409, P3=0.015). Expression of HIF-1α, ANXA3 and CD133 were associated with tumor size, lymphatic metastasis and clinic stage of colon cancer (all P<0.05). Conclusions: HIF-1α, ANXA3 and CD133 were overexpressed in human colon cancer and showed positive correlations among themselves. The expression of HIF-1α, ANXA3 and CD133 were closely related to the size of the tumor, lymphatic metastasis and clinical stage of colon cancer, which indicated that they could be promising biomarkers for the study of colon CSCs and treatment of colon carcinoma.

Pathological complete response in MMR-deficient/MSI-high and KRAS-mutant patient with locally advanced rectal cancer after neoadjuvant chemoradiation with immunotherapy: A case report.

To date, preoperative chemoradiation (CRT) is the standard of care for patients with locally advanced rectal cancer (LARC) regardless of status of mismatch repair. Immunotherapy showed promising results in the neoadjuvant treatment trials in patients with mismatch repair-deficient (dMMR) or high microsatellite instability (MSI-H) LARC. The efficacy of CRT plus programmed death 1 (PD-1) inhibitor in these patients with complex gene mutation remains unclear. Additionally, very few studies reported on whether such combination could induce abscopal effect. We report a case of dMMR and MSI-H LARC with KRAS mutation that achieved pathological complete response of primary lesion and liver metastases after neoadjuvant short-course radiotherapy followed by four cycles chemotherapy of XELOX plus PD-1 inhibitor tislelizumab and a subsequent total mesorectal excision. This case indicates that this combined treatment strategy has remarkable clinical response both in locoregional and distant diseases, which potentially leads to reduction in the risk of distant metastases and better locoregional control for this subgroup of population.

Variation of the ileocolic artery and superior mesenteric artery in a patient with right-sided colon cancer with Lynch syndrome: a case report.

Background: Complete mesangectomy and central vascular detachment are the core elements of laparoscopic right hemicolectomy. Failure to identify vascular variations in patients undergoing laparoscopic right hemicolectomy can result in unwanted bleeding, a prolonged surgical time, transfer to open surgery, and an elevated risk of postoperative complications. In this case report, we describe a new vascular variation that has not yet been reported in the literature. Parallelly vascular variation and the management of vessels in key areas are essential for successful surgery. Case Description: The patient was a 32-year-old female who was referred to the department of gastrointestinal surgery of our hospital due to intermittent abdominal pain accompanied by changes in stool habits for 3 months. She had not experienced other symptoms. Physical examination revealed mild tenderness in the right lower abdomen. Subsequently, she underwent laparoscopic radical right hemicolectomy for ascending colon cancer under general anesthesia in our hospital. Preoperative abdominal contrast-enhanced computed tomography (CT) and intraoperative photos confirmed that there were two ileocolic arteries derived from the superior mesenteric artery (SMA). On the other side, the SMA and superior mesenteric vein (SMV) were found to be accompanied like "X"-shaped variant. The final surgical pathological diagnosis was pT3N1aM0 adenocarcinoma of the ascending colon. Given the patient's family history of colon and uterine cancer combined with the results of immunohistochemical staining and next-generation sequencing, we concluded that she had Lynch syndrome (LS). Conclusions: This report describes the first case of simultaneous variation of the ileocolic artery (ICA) and SMA in a female patient with colon cancer. This type of vascular variation should be fully recognized by surgeons in order to avoid unnecessary intraoperative bleeding.

Analysis of Prognostic Factors of Rectal Cancer and Construction of a Prognostic Prediction Model Based on Bayesian Network.

Background: The existing prognostic models of rectal cancer after radical resection ignored the relationships among prognostic factors and their mutual effects on prognosis. Thus, a new modeling method is required to remedy this defect. The present study aimed to construct a new prognostic prediction model based on the Bayesian network (BN), a machine learning tool for data mining, clinical decision-making, and prognostic prediction. Methods: From January 2015 to December 2017, the clinical data of 705 patients with rectal cancer who underwent radical resection were analyzed. The entire cohort was divided into training and testing datasets. A new prognostic prediction model based on BN was constructed and compared with a nomogram. Results: A univariate analysis showed that age, Carcinoembryonic antigen (CEA), Carbohydrate antigen19-9 (CA19-9), Carbohydrate antigen 125 (CA125), preoperative chemotherapy, macropathology type, tumor size, differentiation status, T stage, N stage, vascular invasion, KRAS mutation, and postoperative chemotherapy were associated with overall survival (OS) of the training dataset. Based on the above-mentioned variables, a 3-year OS prognostic prediction BN model of the training dataset was constructed using the Tree Augmented Naïve Bayes method. In addition, age, CEA, CA19-9, CA125, differentiation status, T stage, N stage, KRAS mutation, and postoperative chemotherapy were identified as independent prognostic factors of the training dataset through multivariate Cox regression and were used to construct a nomogram. Then, based on the testing dataset, the two models were evaluated using the receiver operating characteristic (ROC) curve. The results showed that the area under the curve (AUC) of ROC of the BN model and nomogram was 80.11 and 74.23%, respectively. Conclusion: The present study established a BN model for prognostic prediction of rectal cancer for the first time, which was demonstrated to be more accurate than a nomogram.

Construction of a gut microbiota-gene-pathway network to reveal the molecular mechanisms underlying right- and left-sided colorectal cancer.

Aiming to reveal the molecular mechanisms involved in right- and left-sided colorectal cancer (CRC) development, CRC gene expression data and a microorganism atlas were downloaded from The Cancer Genome Atlas and The Cancer Microbiome Atlas, respectively. The R package was used to screen differentially expressed genes (DEGs) between right- and left-sided CRC samples and identify those related to prognosis, a correlation analysis was performed between DEGs and prognosis-related microbiota, and an interaction network was created using Cytoscape. Finally, a taxon set enrichment analysis of the microbiota was performed and a gene-genus-pathway network was constructed after GO and KEGG analyses. In total, nine out of 1557 identified DEGs had a significant correlation with prognosis, whereas three out of 211 bacterial genera (Fusobacterium, Bacteroides and Parabacteroides) showed a significant correlation with prognosis. DEGs were mainly enriched in the PPAR pathway and vitamin metabolic and transport processes. According to a taxon set enrichment analysis, the microbes in the integrated network were significantly abundant in 28 host-intrinsic, two host-extrinsic and one environment taxon sets. This study provides new insights for understanding the molecular mechanisms of left- and right-CRC.

Transanal Drainage Tube Use for Preventing Anastomotic Leakage After Laparoscopic Low Anterior Resection in Patients With Rectal Cancer: A Randomized Clinical Trial.

Importance: Preventing anastomotic leakage (AL) is crucial for colorectal surgery. Some studies have suggested a positive role of transanal drainage tubes (TDTs) in AL prevention after low anterior resection, but this finding is controversial. Objective: To assess the effect of TDTs in AL prevention after laparoscopic low anterior resection for rectal cancer. Design, Setting, and Participants: This multicenter randomized clinical trial with parallel groups (TDT vs non-TDT) was performed from February 26, 2016, to September 30, 2020. Participants included patients from 7 different hospitals in China who were undergoing laparoscopic low anterior resection with the double-stapling technique for mid-low rectal cancer; 576 patients were initially enrolled in this study, and 16 were later excluded. Ultimately, 560 patients were randomly divided between the TDT and non-TDT groups. Interventions: A silicone tube was inserted through the anus, and the tip of the tube was placed approximately 5 cm above the anastomosis under laparoscopy at the conclusion of surgery. The tube was fixed with a skin suture and connected to a drainage bag. The TDT was scheduled for removal 3 to 7 days after surgery. Main Outcomes and Measures: The primary end point was the postoperative AL rate within 30 days. Results: In total, 576 patients were initially enrolled in this study; 16 of these patients were excluded. Ultimately, 560 patients were randomly divided between the TDT group (n = 280; median age, 61.5 years [IQR, 54.0-68.8 years]; 177 men [63.2%]) and the non-TDT group (n = 280; median age, 62.0 years [IQR, 52.0-69.0 years]; 169 men [60.4%]). Intention-to-treat analysis showed no significant difference between the TDT and non-TDT groups in AL rates (18 [6.4%] vs 19 [6.8%]; relative risk, 0.947; 95% CI, 0.508-1.766; P = .87) or AL grades (grade B, 14 [5.0%] and grade C, 4 [1.4%] vs grade B, 11 [3.9%] and grade C, 8 [2.9%]; P = .43). In the stratified analysis based on diverting stomas, there was no significant difference in the AL rate between the groups, regardless of whether a diverting stoma was present (without stoma, 12 [5.8%] vs 15 [7.9%], P = .41; and with stoma, 6 [8.3%] vs 4 [4.5%], P = .50). Anal pain was the most common complaint from patients in the TDT group (130 of 280, 46.4%). Accidental early TDT removal occurred in 20 patients (7.1%), and no bleeding or iatrogenic colonic perforations were detected. Conclusions and Relevance: The results from this randomized clinical trial indicated that TDTs may not confer any benefit for AL prevention in patients who undergo laparoscopic low anterior resection for mid-low rectal cancer without preoperative radiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02686567.

High Expression of PhospholipaseD2 Induced by Hypoxia Promotes Proliferation of Colon Cancer Cells through Activating NF- κ Bp65 Signaling Pathway.

Hypoxia is a typical feature of colon cancer occurrence and progression. We have reported that high expression and activity of PhospholipaseD2 (PLD2) induced by hypoxia in colon cancer cells. In order to further investigate the role of PLD2 in colon cancer under hypoxic conditions. MTT assay was used to detect the proliferation of human colon cancer cells (SW480 and SW620) under hypoxic conditions by decrease the PLD2 gene expression or inhibit the activity of PLD2. Expression level of p-P65/T-P65 and Cyclin D1 were detected in those cells treated as above through using western blot and RT-PCR analysis. Effect of NF-Bp65 inhibitor (BAY-117082) on the proliferation and expression level of Cyclin D1 and PLD2 of colon cancer cells under hypoxic conditions were further analysised. As a result, decreased the expression of PLD2 or inhibited the activity of PLD2 leaded to the proliferation of hypoxia colon cancer cells reduced, and along with the expression level of p-P65/T-P65 and Cyclin D1 reduced. However, inhibition the expression level of p-P65/T-P65 lead to the proliferation and expression of Cyclin D1 in those hypoxia colon cancer cells also reduced. In vivo growth decreased in response to PLD2 and NF-Bp65 inhibition. Our study indicates that high expression of PLD2 induced by hypoxia promotes the proliferation of colon cancer cells, and it may elevate the expression level of Cyclin D1 through activating NF-Bp65 signaling pathway. Inhibition of the PLD2 expression may provide a new clue for treatment for colon cancer.

ANXA3 is upregulated by hypoxia-inducible factor 1-alpha and promotes colon cancer growth.

BACKGROUND: Annexin A3 (ANXA3) is overexpressed in various cancers and is a potential target for cancer treatment. However, clinical implication and biological function of ANXA3 in colon cancer remain unknown. This study aimed to investigate the relationship between hypoxia-inducible factor 1-alpha (HIF-1α) and ANXA3, and explore the function of ANXA3 in colon carcinoma. METHODS: Expression levels of HIF-1α and ANXA3 in human colon carcinoma specimens and colon cancer cell lines were detected by immunohistochemistry, real-time PCR and Western blot analysis. The proliferation of colon cancer cells was examined. Nude mice were used for xenograft tumor model, and HIF-1α siRNA or control adenovirus was injected into the tumor. RESULTS: HIF-1α and ANXA3 expression levels were higher in colon cancer tissues than their expression levels in normal colon tissues. In addition, HIF-1α and ANXA3 expression increased in colon cancer cells under hypoxic condition. Knockdown of HIF-1α decreased HIF-1α and ANXA3 expression, and inhibited the proliferation and growth of colon cancer cells. In nude mouse model, silencing HIF-1α decreased volume of xenograft tumor and ANXA3 expression. CONCLUSIONS: ANXA3 expression is upregulated by HIF-1α in colon cancer in response to hypoxic stress and contributes to colon tumor growth. ANXA3 may represent a new therapeutic target for colon carcinoma.

Prognostic value of ABO blood group in a Chinese population in Northwest China region with curatively resected rectal cancer.

A positive association between the ABO blood types and survival has been suggested in several malignancies. However, little is known about the relationship between ABO blood group and survival in rectal cancer patients. The aim of this study was to assess the role of the ABO blood types in predicting the prognosis of a Chinese population in Northwest China region with curatively resected rectal cancer. We retrospectively analyzed 1613 consecutive patients who underwent curative surgery for rectal cancer between June, 2011 and December, 2016. The relationship between the ABO blood types and overall survival (OS) was analyzed. The median follow-up period of the 1613 rectal cancer patients was 69.6 months with 1427 alive. There was a significance difference of survival among ABO blood groups (P=0.007). The mean overall survival (OS) of the blood type B patients was 70.8 months, O was 64.3, whereas the mean OS of the AB and A blood type patients was significantly lower, 58.4 months and 59.7 months respectively (P=0.007, log-rank test). Compared with patients with A and AB blood types, patients with blood type B and O were more likely to have better survival(P=0.001). A blood groups were associated with significantly decreased overall survival in rectal cancer patients (hazard ratio = 1.263; 95% confidence interval = 0.776-2.054, P =0.010). In order to confirm our above results, we performed the same investigation in an independent cohort from another hospital of 505 Chinese patients and get the similar results. Our study showed that ABO blood group is associated with survival in Northwest Chinese patients with rectal cancer and the blood type B and O were favourable prognostic factors for patients with rectal cancer.

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.