Intratumor APOL3 delineates a distinctive immunogenic ferroptosis subset with prognosis prediction in colorectal cancer.

With the essential role of lipid transporting signaling in cancer-related immunity, apolipoprotein L3 (APOL3), a member of the apolipoprotein L gene family, demonstrated significant modulation ability in immunity. However, the expression profile and critical role of APOL3 in colorectal cancer (CRC) remain unclear. This study aimed to investigate the prognostic significance of APOL3 expression and its biological predictive value in CRC. The study enrolled multiple cohorts, consisting of 911 tumor microarray specimens of CRC patients from Zhongshan Hospital, 412 transcriptional data from The Cancer Genome Atlas, and 30 single-cell RNA sequencing (scRNA-seq) from internal and external CRC patients. APOL3 mRNA expression was directly acquired from public datasets, and APOL3 protein expression was detected using immunohistochemistry. Finally, the associations of APOL3 expression with clinical outcomes, immune context, and genomic and ferroptotic features were analyzed. Low APOL3 expression predicted poor prognosis and inferior responsiveness to 5-fluorouracil-based adjuvant chemotherapy (ACT) and targeted therapy. APOL3 fosters an immune-active microenvironment characterized by the promotion of ferroptosis, downregulation of macrophages, and upregulation of CD8+ T cell infiltration. Moreover, the expression of APOL3 in CD8+ T cells is intrinsically linked to ferroptosis and immune activation in CRC. In summary, APOL3 serves as an independent prognosticator and predictive biomarker for immunogenic ferroptosis, ACT, and targeted therapy in CRC. Furthermore, the APOL3 signaling activator could be a novel agent alone or in combination with current therapeutic strategies for CRC.

Prognostic Value of Tumor Deposits in Stage III Colorectal Cancer Patients with Different N Stages: A Population-Based, Retrospective, Cohort Study.

PURPOSE: Tumor deposits (TDs) seem to be associated with the prognosis of patients with colorectal cancer (CRC). The goal of this study was to investigate the prognostic value of TDs among patients with stage III CRC at different N stages. METHODS: A retrospective analysis was performed on two independent cohorts of stage III CRC patients from the Surveillance, Epidemiology, and End Results (SEER) database (n = 8232) and the First Affiliated Hospital of Wenzhou Medical University (n = 423). Primary outcomes were overall survival (OS) and cancer-specific survival (CSS). RESULTS: Of 8232 patients in the SEER cohort, the presence of TDs revealed poorer 5-year OS rates and 5-year CSS rates in all N-stage subgroups. X-tile software identified 5 (5-year OS: P = 0.004; 5-year CSS: P < 0.001) as the optimal cutoff value for TD count in the TD-positive subgroup at the N2 stage. The OS (5-year OS: 62.0% vs. 42.0%, P < 0.001) and CSS (5-year CSS: 66.0% vs. 43.8%, P < 0.001) of patients with five or more TDs were significantly worse than those with one to four TDs in the N2 stage subgroups. Of 423 patients in the Wenzhou cohort, the 3-year OS rate for patients in the positive group was worse than that for patients in the negative group (88.7% vs. 94.3%, P = 0.015). CONCLUSIONS: TD count should be considered when evaluating the prognosis of patients with the N2 stage. Those with higher TD counts (≥ 5) might have a worse prognosis.

A novel lncRNA LOC101927746 accelerates progression of colorectal cancer via inhibiting miR-584-3p and activating SSRP1.

An increasing number of reports have indicated that long noncoding RNAs (lncRNAs) are involved in the pathogenesis of colorectal cancer (CRC). However, many lncRNAs remain unidentified in CRC, and their functions are yet to be elucidated. In this study, we investigated the function of lncRNA LOC101927746 in CRC progression. We found that LOC101927746 expression was significantly increased in CRC tissues according to the GEO dataset. Moreover, LOC101927746 expression was positively correlated with tumor stage and metastasis. Additionally, the high expression of LOC101927746 predicted poor prognosis in CRC patients. Functionally, we demonstrated that LOC101927746 silencing significantly suppressed the proliferation, migration, and invasion of CRC cells. In terms of its mechanism, LOC101927746 could serve as a competing endogenous RNA to inhibit miR-584-3p and activate its target gene SSRP1. The expression of miR-584-3p was inversely correlated with either LOC101927746 or SSRP1 in CRC tissues. The overexpression of SSRP1 or inhibition of miR-584-3p could reverse the effects of LOC101927746 knockdown in CRC cells. Taken together, our results suggest that the LOC101927746/miR-584-3p/SSRP1 axis modulates CRC progression.

Rapamycin Promotes the Survival and Adipogenesis of Ischemia-Challenged Adipose Derived Stem Cells by Improving Autophagy.

BACKGROUND/AIMS: Ischemia is one of the main causes of the high rate of absorption of transplanted autologous fat. Autophagy allows cells to survive by providing energy under starvation. Rapamycin has been found to play a role in promoting autophagy. In this study, we investigated whether rapamycin participates in the survival and adipogenesis of ischemia-challenged adipose-derived stem cells (ADSCs) by regulating autophagy. METHODS: Before the cells were exposed to oxygen-glucose deprivation (OGD), a simulated ischemic microenvironment, the level of autophagy was reduced or increased by lentiviral transfection with short hairpin RNA targeting microtubule-associated protein 1-light chain 3 gene (shRNA-LC3) or treatment with rapamycin, respectively. The level of autophagy was assessed by western blotting, transmission electron microscopythen the apoptosis ratio was determined through terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and flow cytometry. Adipogenesis was further evaluated by oil red O staining and the expressions level of some specific proteins for adipocytes. RESULTS: shRNA-LC3 and rapamycin treatment effectively decreased and improved the level of autophagy in cells with or without OGD challenge, respectively. In addition, autophagy inhibition increased the apoptosis rate and activated caspase-3 expression level in response to OGD, and these were markedly inhibited by rapamycin preconditioning. During adipogenesis, autophagy inhibition decreased not only oil droplet accumulation but also lipoprotein lipase (LPL) and peroxisome proliferator-activated receptor gamma (PPARγ) expression in cells with or without OGD challenge. However, autophagy promotion by rapamycin increased oil droplet accumulation and LPL and PPARγ expression. CONCLUSIONS: Rapamycin may promote the survival and adipogenesis of ischemia-challenged ADSCs by upregulating autophagy.

Induction of autophagy by salidroside through the AMPK-mTOR pathway protects vascular endothelial cells from oxidative stress-induced apoptosis.

Vascular endothelial cells are highly sensitive to oxidative stress, and this is one of the mechanisms by which widespread endothelial dysfunction is induced in most cardiovascular diseases and disorders. However, how these cells can survive in oxidative stress environments remains unclear. Salidroside, a traditional Chinese medicine, has been shown to confer vascular protective effects. We aimed to understand the role of autophagy and its regulatory mechanisms by treating human umbilical vein endothelial cells (HUVECs) with salidroside under oxidative stress. HUVECs were treated with salidroside and exposed to hydrogen peroxide (H2O2). The results indicated that salidroside exerted cytoprotective effects in an H2O2-induced HUVEC injury model and suppressed H2O2-induced apoptosis of HUVECs. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, increased oxidative stress-induced HUVEC apoptosis, while the autophagy activator rapamycin induced anti-apoptosis effects in HUVECs. Salidroside increased autophagy and decreased apoptosis of HUVECs in a dose-dependent manner under oxidative stress. Moreover, 3-MA attenuated salidroside-induced HUVEC autophagy and promoted apoptosis, whereas rapamycin had no additional effects compared with salidroside alone. Salidroside upregulated AMPK phosphorylation but downregulated mTOR phosphorylation under oxidative stress; however, administration of compound C, an AMPK inhibitor, abrogated AMPK phosphorylation and increased mTOR phosphorylation and apoptosis compared with salidroside alone. These results suggest that autophagy is a protective mechanism in HUVECs under oxidative stress and that salidroside might promote autophagy through activation of the AMPK pathway and downregulation of mTOR pathway.

Randomized Controlled Trial of Intraportal Chemotherapy Combined With Adjuvant Chemotherapy (mFOLFOX6) for Stage II and III Colon Cancer.

OBJECTIVES: The optimal time to initiate adjuvant chemotherapy after surgery in patients with colon cancer is not clear. We investigated the benefit of combined intraportal chemotherapy administered during radical surgery with adjuvant chemotherapy for treating stage II and III colon cancer. METHODS: Patients were randomly assigned to OCTREE arm (intraportal chemotherapy plus mFOLFOX6) or a standard adjuvant chemotherapy arm (mFOLFOX6). The primary study endpoint was disease-free survival. The secondary endpoints included metastasis-free survival, overall survival, and safety. RESULTS: The intent-to-treat population comprised 237 patients. With a median follow-up of 44 months, the hazard ratio (OCTREE vs mFOLFOX6) was 0.66 (95% confidence interval, 0.43-0.90), a 34% risk reduction in favor of OCTREE (P = 0.016). The 3-year disease-free survival rate was 85.2% for OCTREE and 75.6% for mFOLFOX6 alone (P = 0.030). The 3-year metastasis-free survival rates were 87.6% for OCTREE and 78.0% for mFOLFOX6 (P = 0.035). Patients had lower distant metastatic rate in the OCTREE arm (12.7% vs 22.7%; P = 0.044), when compared with the mFOLFOX6 arm. The 3-year overall survival was no significant difference between 2 arms (P = 0.178). Neutropenia occurred in 12.7% of the patients receiving OCTREE and in 2.5% of the patients receiving mFOLFOX6 (P = 0.003) within 2 weeks of surgery, and grade 3 or 4 toxicity event was no difference between 2 regimens. CONCLUSIONS: Combination of intraoperative intraportal chemotherapy with mFOLFOX6 reduced the occurrence of distant metastases and improved disease-free survival in patients with stage II and stage III colon cancer.

Downregulation of paraoxonase 3 contributes to aggressive human hepatocellular carcinoma progression and associates with poor prognosis.

Paraoxonase (PON) enzymes possess antioxidant properties and protect against cardiovascular diseases. As a member of PON family, PON3 is primarily synthesized in the liver and poorly investigated. This study aimed to examine the expression of PON3 in human hepatocellular carcinoma (HCC) and investigate the clinical significance and biological function of PON3 in HCC patients. We first analyzed PON3 expression in 50 paired HCC samples (HCC tissues vs matched para-cancerous tissues) and 160 clinical HCC specimens by using immunohistochemistry (IHC). Our results showed that the expression of PON3 was downregulated in HCC and significantly associated with tumor-node-metastasis (TNM) stage, tumor size, and tumor number. Kaplan-Meier survival and Cox regression analyses showed that PON3 was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR). Finally, we aimed to reveal the biological function of PON3 in HCC growth and metastasis, and our results showed that overexpression of PON3 potently inhibited growth and metastasis of HCC. Collectively, our study demonstrated that PON3 exhibited tumor-suppressive effects toward HCC and it might serve as a novel prognostic marker in HCC.

Clinicopathological significance and potential drug target of O6-methylguanine-DNA methyltransferase in colorectal cancer: a meta-analysis.

Emerging evidence indicates that O(6)-methylguanine-DNA methyltransferase (MGMT) is a candidate for tumor suppression in several types of human tumors including colorectal cancer (CRC). However, the correlation between MGMT hypermethylation and clinicopathological characteristics of CRC remains unclear. In this study, we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of MGMT hypermethylation on the incidence of CRC and clinicopathological characteristics. A comprehensive literature search was done from Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, and the Chinese Biomedical Database for related research publications written in English and Chinese. Methodological quality of the studies was also evaluated. Analyses of pooled data were performed with Review Manager 5.2. Odds ratio (OR) and hazard ratio (HR) were calculated and summarized, respectively. Final analysis from 28 eligible studies was performed. MGMT hypermethylation is found to be significantly higher in CRC than in normal colorectal mucosa, the pooled OR from 13 studies including 1085 CRC and 899 normal colorectal mucosa, OR = 6.04, 95 % confidence interval (CI) = 4.69-7.77, p < 0.00001. MGMT hypermethylation is also significantly higher in colorectal adenoma than in normal colorectal mucosa, but it is significantly less compared to that in CRC patients. Interestingly, MGMT hypermethylation is correlated with sex status and is significantly higher in female than in male. MGMT hypermethylation is also associated with high levels of microsatellite instability (MSI). The pooled HR for overall survival (OS) shows that MGMT hypermethylation is not associated with worse survival in CRC patients. The results of this meta-analysis suggest that MGMT hypermethylation is associated with an increased risk and high levels of MSI and may play an important role in CRC initiation. However, MGMT hypermethylation may play an important role in the early stage of CRC progression and development, as well as having limited value in prediction of prognosis in CRC patients. We also discussed that MGMT may serve as a potential drug target of CRC.

Aberrant expression of long noncoding RNAs in colorectal cancer with liver metastasis.

Long noncoding RNA (lncRNA) plays a crucial role in the regulation of various cellular processes and human diseases. However, little is known about the role of lncRNAs in colorectal liver metastasis (CLM). In the present study, we aimed to determine whether lncRNAs are differentially expressed in CLM tissue and to further assess their clinical value. lncRNA arrays were employed to screen for differentially expressed lncRNAs in colorectal cancer (CRC) tissues with synchronous, metachronous, or nonliver metastasis. Based on bioinformatics data, a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay was performed to identify target lncRNAs in an expanded set of CRC samples with various subtypes of liver metastasis. The relationships between the target lncRNAs and the clinical characteristics and patient prognosis were further analyzed. After determining the expression profile of lncRNAs (n = 1332) in CLM tissue, 40 differentially expressed lncRNAs that were potentially related to CLM were selected for further examination in an expanded set of clinical samples, and three novel target lncRNAs, termed lncRNA-CLMAT1-3, were verified. High lncRNA-CLMAT3 expression strongly correlated with liver metastasis (P = 0.03) and lymph node metastasis (P = 0.009). Moreover, patients displaying high lncRNA-CLMAT3 expression exhibited a shorter median overall survival duration than those displaying low lncRNA-CLMAT3 expression (30.7 vs. 35.2 months, P = 0.007). Multivariate analysis demonstrated that the lncRNA-CLMAT3 expression level is an independent prognostic factor (hazard ratio 2.05, P = 0.02) after adjusting for other known prognostic factors. lncRNA-CLMAT3 over-expression was significantly associated with CLM and was an independent predictor of poor survival for patients with CRC.

Comparison of minimally invasive and open colorectal resections for patients undergoing simultaneous R0 resection for liver metastases: a propensity score analysis.

PURPOSE: The role of minimally invasive colorectal resection for patients undergoing a simultaneous resection for synchronous liver metastases had not been established. This study compared the short- and long-term outcomes between minimally invasive and open colorectal resection for patients undergoing simultaneous resection for liver metastases. METHODS: This study reviewed 101 consecutive patients undergoing simultaneous colorectal resection and R0 resection of synchronous liver metastases between January 2008 and December 2012. In the study, 36 consecutive patients who underwent minimally invasive colorectal resection were matched with 36 patients who had an open approach by propensity scoring. The analyzed variables included patient and tumor characteristics and short-term and long-term outcomes. RESULTS: After propensity score matching, the two groups had similar clinicopathologic variables. No patient undergoing the minimally invasive procedure experienced conversion to the open technique. No postoperative mortality occurred in either group. In the minimally invasive group, the estimated blood loss (P < 0.007), bowel function return time (P < 0.016), and postoperative hospital stay (P < 0.011) were significantly lower than those in the open group, although the operating time was significantly longer (P < 0.001). No significant differences in postoperative complications were observed between the groups. The two groups did not differ significantly in terms of the 5-year overall survival rate (51 vs. 55 %; P = 0.794) and disease-free survival rate (38 vs. 27 %; P = 0.860). CONCLUSION: Minimally invasive colorectal resection with simultaneous resection of liver metastases has an outcome similar to open approach but some short-term advantages.

Impact of early tumor shrinkage on clinical outcome in wild-type-KRAS colorectal liver metastases treated with cetuximab.

BACKGROUND AND AIM: To evaluate the impact of early tumor shrinkage (ETS) on long-term outcome in patients with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) unresectable colorectal liver metastases (CLM) receiving cetuximab plus chemotherapy. METHODS: A total of 138 patients in a randomized controlled trial (70 in armA received cetuximab plus chemotherapy, 68 in armB received chemotherapy alone), as previously reported (Ye et al., 2013) were included into this analysis. The cut-off date updated for overall survival (OS) was June 2014. ETS was defined as a ≥ 20% reduction of the longest diameters of the target lesions compared with baseline at the first evaluation (8 weeks). Outcome measures were progression-free survival (PFS) and OS. RESULTS: There were 132 patients available for evaluation, and ETS occurred more frequently in armA than that in armB (P = 0.003). ETS was associated with longer OS (armA: 35.7 vs. 19.5 months, P < 0.001; armB 28.7 vs. 18.7 months, P = 0.01) and PFS (armA: 13.4 vs. 4.2 months, P < 0.001; armB 7.0 vs. 4.2 months, P = 0.001) compared with patients with no-ETS. Among patients with ETS, there was a significant difference between armA and armB in PFS (P = 0.03), but not in OS (P = 0.19). All 23 patients who underwent liver surgery achieved ETS. In armA, for patients without liver surgery, patients observed ETS also gained an increased survival benefit over those no-ETS in OS (P = 0.02) and PFS (P < 0.001). ETS was an independent predictor of improved OS (hazard ratio 0.56, P = 0.007). CONCLUSION: ETS may serve as a predictor of favorable outcome in patients with wild-type KRAS CLM receiving cetuximab plus chemotherapy.

Short-term quality of life in patients undergoing colonic surgery using enhanced recovery after surgery program versus conventional perioperative management.

OBJECTIVE: Enhanced recovery after surgery (ERAS) integrates evidence-based interventions to reduce surgical stress and accelerate rehabilitation. Our study was to compare the short-term quality of life (QOL) in patients undergoing open colonic surgery using ERAS program or conventional management. METHODS: A prospective study of 57 patients using ERAS program and 60 patients using conventional management was conducted. The clinical characteristics of all patients were recorded. QOL was evaluated longitudinally using the questionnaires (EORTC QLQ-C30 and QLQ-CR29) pre- and postoperatively. Generalized estimating equation was used to do the analysis in order to determine the effective impact of correlative factors on the postoperative QOL, including age, sex, BMI, ASA grade, tumor location, tumor size, pTNM stage, recovery program and length of time after surgery. RESULTS: The morbidity in ERAS and control group was 17.5 versus 26.7 % (p = 0.235). The patients in ERAS group had much faster rehabilitation and less hospital stay. In the primary statistical analysis, the scores of global QOL (on POD3, POD6, POD10, POD14, POD21), physical functioning (on POD3, POD6, POD10, POD14, POD21), role functioning (on POD6, POD10, POD14, POD21), emotional functioning (on POD3, POD6, POD10, POD14, POD21), cognitive functioning (on POD3, POD6) and social functioning (on POD3, POD6, POD10, POD14, POD21, POD28) were higher in ERAS group than in control group, which suggested that the patients in ERAS group had a better life status. However, the scores of pain (on POD10, POD14, POD21), appetite loss (on POD3, POD6), constipation (on POD3, POD6, POD10), diarrhea (on POD3, POD10), financial difficulties (on POD10, POD14, POD21), perspective of future health (on POD6, POD10, POD14), gastrointestinal tract problems (on POD3, POD6, POD10) and defecation problems (on POD6, POD10, POD14) were lower in ERAS group than in control group, which revealed that the patients in ERAS group suffered less symptoms. In the further generalized estimating equation analysis, the result showed that recovery program and length of time after surgery had independently positive impact on the patient's postoperative QOL. CONCLUSION: Short-term QOL in patients undergoing colonic cancer using ERAS program was better than that using conventional management.

Overexpression of long non-coding RNA HOTAIR predicts poor patient prognosis and promotes tumor metastasis in epithelial ovarian cancer.

OBJECTIVES: Although long non-coding RNAs (lncRNAs) are emerging as new regulators in the cancer paradigm, the involvement of lncRNAs in epithelial ovarian cancer (EOC) is just beginning to be studied. In this study, we focused on lncRNA HOX transcript antisense RNA (HOTAIR) and investigated its expression pattern, clinical significance, and biological function in EOC. METHODS: HOTAIR expression in EOC tissues was examined and its correlation with clinicopathological factors and patient prognosis was analyzed. A series of in vitro and in vivo assays were performed to understand the role of HOTAIR in EOC metastasis. RESULTS: HOTAIR expression was elevated in EOC tissues, and HOTAIR levels were highly positively correlated with the FIGO stage, the histological grade of the tumor, lymph node metastasis, and reduced overall survival (OS) and disease-free survival (DFS). A multivariate analysis showed that HOTAIR expression is an independent prognostic factor of OS and DFS in patients with EOC. Additionally, the results of in vitro assays showed that the suppression of HOTAIR expression in the three highly metastatic EOC cell lines (SKOV3.ip1, HO8910-PM, and HEY-A8) significantly reduced cell migration/invasion. The results of in vivo assays further confirmed the pro-metastatic effects of HOTAIR. Moreover, the pro-metastatic effects of HOTAIR were partially mediated by the regulation of certain matrix metalloproteinases (MMPs) and epithelial-to-mesenchymal transition (EMT)-related genes. CONCLUSIONS: Our data suggest that HOTAIR plays a vital role in EOC metastasis and could represent a novel prognostic marker and potential therapeutic target in patients with EOC.

Estimating Efficacy of Conversion Therapy on Patients with Initially Unresectable Colorectal Cancer Liver Metastases by using MRI: Development of a Predictive Score.

RATIONALE AND OBJECTIVES: The conversion success rate (CSR) has crucial implication for clinical outcomes of initially unresectable colorectal liver metastases (CRLM) following conversion therapy. This study aimed to develop a simple predictive scoring model for identifying CSR according to baseline magnetic resonance imaging (MRI) features, and confirm its performance and prognostic significance in a validation cohort. METHODS: A total of 155 consecutive patients with initially unresectable CRLM were retrospectively reviewed in the study. A simple MRI-based predictive scoring model for identifying CSR was developed in the development cohort (n = 104) by using multivariable logistic regression analyzes. The diagnostic performance was evaluated for the predictive score. Thereafter, patients in the validation cohort (n = 51) were stratified into groups with predicted high CSR or low CSR according to the score. The progression-free survival (PFS) and overall survival (OS) were compared between two groups using the log-rank test. RESULTS: The predictive score of CSR, named mrNISE, incorporated the number of CRLM ≥ 10, the largest size ≥ 50 mm, poorly defined tumor-liver interface, and peritumoral enhancement. The AUC of the mrNISE score was 0.845 for the development cohort and 0.776 for the validation cohort. According to the score, patients with predicted high CSR had better PFS and OS than those with low CSR in both development and validation cohorts. CONCLUSION: The predictive score demonstrated great performance for identifying CSR of initially unresectable CRLM. Stratifying patients by the score, personalized treatment goals can be formulated before conversion therapy to improve clinical prognosis and reduce adverse events caused by ineffective treatment.

VIC Regimen (Vemurafenib/Irinotecan/Cetuximab) Versus Bevacizumab Plus Chemotherapy as First-Line Treatment for BRAF V600E-Mutated Unresectable or Metastatic Colorectal Cancer in Asian Patients: A Prospective Cohort Study.

BACKGROUND: Colorectal cancers (CRC) with BRAF V600E mutation exhibit limited chemotherapy response and a poor prognosis. Safety and efficacy of the VIC (Vemurafenib/Irinotecan/Cetuximab) regimen in the first-line setting for patients with BRAF V600E-mutated CRC remain undetermined. METHODS: In the prospective cohort study, the untreated, BRAF V600E-mutated, unresectable or metastatic CRC patients were enrolled. The VIC regimen and bevacizumab plus chemotherapy were compared in the first-line setting. The objective response rate (ORR), disease control rate (DCR), conversion resection rate, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: In the intent-to-treat analysis, 38 patients received VIC regimen and 40 received bevacizumab plus chemotherapy. The ORR and DCR in the VIC group were significantly higher than in the bevacizumab-therapy group (ORR: 63.2% vs. 37.5%, P = .025; DCR: 94.7% vs. 75.0%, P = .019). The VIC regimen significantly outperformed bevacizumab plus chemotherapy in both PFS (11.9 vs. 7.7 months; hazard ratio [HR] = 0.51, 95% CI, 0.30-0.87; P = .010) and OS (25.3 vs. 14.6 months; HR = 0.43, 95% CI, 0.22-0.82; P = .011). In the VIC group, the conversion resection rate for liver metastases was 34.8% (8 of 23 patients), and for unresectable local CRC it was 54.5% (6 of 11 patients). The adverse events rates of Grade 3 to 4 were 34.2% and 32.5% for the VIC regimen and bevacizumab plus chemotherapy respectively. CONCLUSIONS: Among Asian patients with BRAF V600E-mutated CRC, the VIC regimen showed favorable outcomes compared to bevacizumab plus chemotherapy in terms of tumor response and oncological survival, with a tolerable and manageable toxicity profile in the first-line setting.

Predicting metachronous liver metastasis from colorectal cancer using serum proteomic fingerprinting.

BACKGROUND: There are currently no accurate predictive markers of metachronous liver metastasis (MLM) from colorectal cancer. METHODS: Magnetic bead-based fractionation coupled with mass spectrometry analysis was used to compare serum samples from 64 patients with MLM and 64 without recurrence or metastasis for at least 3 y after radical colorectal surgery (NM). A total of 40 MLM and 40 NM serum samples were randomly selected to build a decision tree, and the remainder were tested as blinded samples. Selected peptides were identified. RESULTS: The patients in the two groups were matched for gender, age, tumor location, TNM staging, and histologic differentiation grade. Preoperative serum carcinoembryonic antigen retained no independent power to predict MLM. The decision tree model with eight proteomic features (m/z 3315, 6637, 1207, 1466, 4167, 4210, 2660, and 4186) correctly classified 33 of 40 NM sera (82.5%) and 32 of 40 MLM sera (80%) in the training set and 19 of 24 NM sera (79.2%) and 17 of 24 MLM sera (70.8%) in the test set. The peptides were identified as fragments of alpha-fetoprotein, complement C4-A, fibrinogen alpha, eukaryotic peptide chain release factor GTP-binding subunit ERF3B, and angiotensinogen. CONCLUSIONS: In patients matched for gender, age, tumor location, TNM staging, and histologic differentiation grade, preoperative carcinoembryonic antigen retained no independent power to predict MLM. The decision tree model of eight proteomic features demonstrated promising value for predicting MLM in patients who underwent radical resection of colorectal cancer.

The Role of RNA Methylation Modification Related Genes in Prognosis and Immunotherapy of Colorectal Cancer.

Background: Researches showed RNA methylation genes can affect the prognosis of tumors. Thus, the study aimed to comprehensively analyze the effects of RNA methylation regulatory genes in prognosis and treatment of colorectal cancer (CRC). Methods: Prognostic signature associated with CRCs were constructed by differential expression analysis, Cox and Least Absolute Shrinkage and Selection Operator (LASSO) analyses. Receiver operating characteristic (ROC) and Kaplan-Meier survival analyses were used to validate the reliability of the developed model. Gene Ontology (GO), Gene set variation analysis (GSVA), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed for functional annotation. Finally, normal and cancerous tissue were collected to validate gene by quantitative real-time PCR (qRT-PCR). Results: A prognostic risk model based on leucine rich pentatricopeptide repeat containing (LRPPRC) and ubiquitin-like with PHD and ring finger domains 2 (UHRF2) was constructed and relevant to the overall survival (OS) of CRC. Functional enrichment analysis revealed that collagen fibrous tissue, ion channel complex and other pathways were significantly enriched, which might help explain the underlying molecular mechanisms. There were significant differences in ImmuneScore, StromalScore, ESTIMATEScore between high- and low-risk groups (p < 0.05). Ultimately, qRT-PCR validation showed that a significant upregulation in the expression of LRPPRC and UHRF2 in cancerous tissue, which verified the effectiveness of our signature. Conclusion: In conclusion, 2 prognostic genes (LRPPRC and UHRF2) related to RNA methylation were identified by bioinformatics analysis, which might supply a new insight into the treatment and evaluation of CRC.

Inhibition of thioredoxin-1 enhances the toxicity of glycolysis inhibitor 2-deoxyglucose by downregulating SLC1A5 expression in colorectal cancer cells.

BACKGROUND: Targeting glycolysis in cancer is an attractive approach for therapeutic intervention. 2-Deoxyglucose (2DG) is a synthetic glucose analog that inhibits glycolysis. However, its efficacy is limited by the systemic toxicity at high doses. Understanding the mechanism of 2DG resistance is important for further use of this drug in cancer treatment. METHODS: The expression of thioredoxin-1 (Trx-1) in colorectal cancer (CRC) cells treated with 2DG was detected by Western blotting. The effect of Trx-1 on the cytotoxicity of 2DG in CRC cells was examined in vitro and in vivo. The molecular mechanism involved in Trx-1-mediated activation of the SLC1A5 gene promoter activity was elucidated using in vitro models. RESULTS: Inhibition glycolysis with 2DG increased the expression of Trx-1 in CRC cells. Overexpression of Trx-1 decreased the cytotoxicity of 2DG, whereas knockdown of Trx-1 by shRNA significantly increased the cytotoxicity of 2DG in CRC cells. The Trx-1 inhibitor PX-12 increased the cytotoxicity of 2DG on CRC cells both in vitro and in vivo. In addition, Trx-1 promoted SLC1A5 expression by increasing the promoter activity of the SLC1A5 gene by binding to SP1. We also found that the SLC1A5 expression was upregulated in CRC tissues, and inhibition of SLC1A5 significantly enhanced the inhibitory effect of 2DG on the growth of CRC cells in vitro and in vivo. Overexpression of SLC1A5 reduced the cytotoxicity of 2DG in combination with PX-12 treatment in CRC cells. CONCLUSION: Our results demonstrate a novel adaptive mechanism of glycolytic inhibition in which Trx-1 increases GSH levels by regulating SLC1A5 to rescue cytotoxicity induced by 2DG in CRC cells. Inhibition of glycolysis in combination with inhibition of Trx-1 or SLC1A5 may be a promising strategy for the treatment of CRC.