Metabolic enzymes have an indispensable role in metabolic reprogramming, and their aberrant expression or activity has been associated with chemosensitivity. Hence, targeting metabolic enzymes remains an attractive approach for treating tumors. However, the influence and regulation of cysteine desulfurase (NFS1), a rate-limiting enzyme in iron–sulfur (Fe–S) cluster biogenesis, in colorectal cancer (CRC) remain elusive. Here, using an in vivo metabolic enzyme gene-based clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 library screen, we revealed that loss of NFS1 significantly enhanced the sensitivity of CRC cells to oxaliplatin. In vitro and in vivo results showed that NFS1 deficiency synergizing with oxaliplatin triggered PANoptosis (apoptosis, necroptosis, pyroptosis, and ferroptosis) by increasing the intracellular levels of reactive oxygen species (ROS). Furthermore, oxaliplatin-based oxidative stress enhanced the phosphorylation level of serine residues of NFS1, which prevented PANoptosis in an S293 phosphorylation-dependent manner during oxaliplatin treatment. In addition, high expression of NFS1, transcriptionally regulated by MYC, was found in tumor tissues and was associated with poor survival and hyposensitivity to chemotherapy in patients with CRC. Overall, the findings of this study provided insights into the underlying mechanisms of NFS1 in oxaliplatin sensitivity and identified NFS1 inhibition as a promising strategy for improving the outcome of platinum-based chemotherapy in the treatment of CRC.

Acidosis is a significant feature of the tumor microenvironment in glioma, and it is closely related to multiple biological functions of cancer stem cells. Here, we found that the self-renewal ability, the mitochondrial activity and ATP production were elevated in stem cell-like glioma cells (SLCs) under acidic microenvironment, which promoted and maintained the stemness of SLCs. Under acidosis, 25-hydroxy vitamin D3-24-hydroxylase (CYP24A1) was upregulated and catalyzed the fast degradation of 1α,25(OH)2D3. We further revealed that the active form of vitamin D (1α,25(OH)2D3) could inhibit the expression of stemness markers, attenuate acidosis-induced increase of self-renewal ability and mitochondrial respiration in stem cell-like glioma cells. Our study indicates that the acidosis–CYP24A1–vitamin D pathway may be a key regulator of the cancer stem cell phenotype in malignant glioma and point out the potential value for the utilization of vitamin D to target cancer stem cells and to restrain the growth of malignant glioma in the future.

Background : Lymphocytes were reported to play a significant part in host anticancer immune responses and influence tumour prognosis. Few studies have focused on the prognostic values of aspartate aminotransferase (AST) to lymphocyte ratio (ALRI), aspartate aminotransferase to platelet count ratio index (APRI) and systemic immune-inflammation index (SII) in hepatocellular carcinoma (HCC) treated with palliative treatments. Methods : Five hundred and ninety-eight HCC patients treated with palliative therapies were retrospectively analysed. We randomly assigned patients into the training cohort (429 patients) and the validation cohort I (169 patients). Receiver operating characteristic (ROC) curves were used to identify the best cut-off values for the ALRI, APRI and SII in the training cohort and the values were further validated in the validation cohort I. Correlations between ALRI and other clinicopathological factors were also analysed. A prognostic nomogram including ALRI was established. We validated the prognostic value of the ALRI, SII and APRI with two independent cohorts, the validation cohort II of 82 HCC patients treated with TACE and the validation cohort III of 150 HCC patients treated with curative resection. In the training cohort and all the validation cohorts, univariate analyses by the method of Kaplan-Meier and multivariate analysis by Cox proportional hazards regression model were carried out to identify the independent prognostic factors. Results : The threshold values of ALRI, APRI and SII were 86.3, 1.37 and 376.4 respectively identified by ROC curve analysis in the training cohort. Correlation analysis showed that ALRI>86.3 was greatly associated with higher rates of Child-Pugh B&C, portal vein tumor thrombosis (PVTT) and ascites ( P < 0.05). Correspondingly, ALRI level of HCC patients with Child-Pugh B&C, PVTT and ascites was evidently higher than that of HCC patients with Child-Pugh A, without PVTT and without ascites ( P < 0.001). In the training cohort and the validation cohort I, II, III, the OS of patients with ALRI >86.3 was obviously shorter than patients with ALRI ≤86.3 ( P < 0.001). We identified ALRI as an independent prognostic factor by univariate and multivariate analyses both in training Cohort (HR=1.481, P= 0.004), validation cohort I (HR=1.511, P= 0.032), validation cohort II (HR=3.166, P= 0.005) and validation cohort III (HR=3.921, P= 0.010). The SII was identified as an independent prognostic factor in training cohort (HR=1.356, P= 0.020) and the validation cohort II (HR=2.678, P= 0.002). The prognostic nomogram including ALRI was the best in predicting 3-month, 6-month, 1-year, 2-year survival And OS among TNM, ALRI, ALRI-TNM and nomogram. Conclusions : The ALRI was a novel indep...

Long noncoding RNAs (lncRNA) are involved in tumorigenesis and drug resistance. However, the roles and underlying mechanisms of lncRNAs in colorectal cancer are still unknown. In this work, through transcriptomic profiling analysis of 21 paired tumor and normal samples, we identified a novel colorectal cancer–related lncRNA, MNX1-AS1. MNX1-AS1 expression was significantly upregulated in colorectal cancer and associated with poor prognosis. In vitro and in vivo gain- and loss-of-function experiments showed that MNX1-AS1 promotes the proliferation of colorectal cancer cells. MNX1-AS1 bound to and activated Y-box-binding protein 1 (YB1), a multifunctional RNA/DNA-binding protein, and prevented its ubiquitination and degradation. A marked overlap between genes that are differentially expressed in MNX1-AS1 knockdown cells and transcriptional targets of YB1 was observed. YB1 knockdown mimicked the loss of viability phenotype observed upon depletion of MNX1-AS1. In addition, MYC bound the promoter of the MNX1-AS1 locus and activated its transcription. In vivo experiments showed that ASO inhibited MNX1-AS1, which suppressed the proliferation of colorectal cancer cells in both cell-based and patient-derived xenograft models. Collectively, these findings suggest that the MYC–MNX1-AS1–YB1 axis might serve as a potential biomarker and therapeutic target in colorectal cancer. Significance: This study highlights the discovery of a novel colorectal cancer biomarker and therapeutic target, MNX1-AS1, a long noncoding RNA that drives proliferation via a MYC/MNX1-AS1/YB1 signaling pathway.

Background: Deregulation of protein translation control is a hallmark of cancers. Eukaryotic initiation factor 4A2 (EIF4A2) is required for mRNA binding to ribosome and plays an important role in translation initiation. However, little is known about its functions in colorectal cancer (CRC). Methods: Analysis of CRC transcriptome data from TCGA identified that EIF4A2 was associated with poor prognosis. Immunohistochemistry study of EIF4A2 was carried out in 297 paired colorectal tumor and adjacent normal tissue samples. In vitro and in vivo cell-biological assays were performed to study the biological functions of EIF4A2 on experimental metastasis and sensitivity to oxaliplatin treatment. Bioinformatic prediction, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay were carried out to unveil the transcription factor of EIF4A2 regulation. Results: EIF4A2 Expression is significantly higher in colorectal tumors. Multivariate analysis suggests EIF4A2 as an independent predictor of overall, disease-free and progression-free survival. Dysfunction of EIF4A2 by genetic knock-down or small-molecule inhibitor silvestrol dramatically inhibited CRC invasion and migration, sphere formation and enhanced sensitivity to oxaliplatin treatment in vitro and in vivo. Notably, EIF4A2 knock-down also suppressed lung metastasis in vivo. qRT-PCR and immunoblotting analyses identified c-Myc as a downstream target and effector of EIF4A2. ChIP and dual-luciferase reporter assays validated the bioinformatical prediction of ZNF143 as a specific transcription factor of EIF4A2. Conclusions: EIF4A2 promotes experimental metastasis and oxaliplatin resistance in CRC. Silvestrol inhibits tumor growth and has synergistic effects with oxaliplatin to induce apoptosis in cell-derived xenograft (CDX) and patientderived xenograft (PDX) models.