KIAA1549 promotes the development and chemoresistance of colorectal cancer by upregulating ERCC2.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Chemotherapy is the mainstay of treatment for patients with CRC in II-IV stages. Resistance to chemotherapy occurs commonly, which results in treatment failure. Therefore, the identification of novel functional biomarkers is essential for recognizing high-risk patients, predicting recurrence, and developing new therapeutic strategies. Herein, we assessed the roles of KIAA1549 in promoting tumor development and chemoresistance in colorectal cancer. As a result, we found that KIAA1549 expression is up-regulation in CRC. Public databases revealed a progressive up-regulation of KIAA1549 expression from adenomas to carcinomas. Functional characterization uncovered that KIAA1549 promotes tumor malignant phenotypes and boosts the chemoresistance of CRC cells in an ERCC2-dependent manner. Inhibition of KIAA1549 and ERCC2 effectively enhanced the sensitivity to chemotherapeutic drugs oxaliplatin and 5-fluorouracil. Our findings suggest that endogenous KIAA1549 might function as a tumor development-promoting role and trigger chemoresistance in colorectal cancer partly by upregulating DNA repair protein ERCC2. Hence, KIAA1549 could be an effective therapeutic target for CRC and inhibition of KIAA1549 combined with chemotherapy might be a potential therapeutic strategy in the future.

Targeting MS4A4A on tumour-associated macrophages restores CD8+ T-cell-mediated antitumour immunity.

OBJECTIVE: Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly expressed in tumour-associated macrophages (TAMs). Here, we aimed to reveal the role of MS4A4A+ TAMs in regulating the immune escape of tumour cells and to develop novel therapeutic strategies targeting TAMs to enhance the efficacy of immune checkpoint inhibitor (ICI) in colorectal cancer. DESIGN: The inhibitory effect of MS4A4A blockade alone or combined with ICI treatment on tumour growth was assessed using murine subcutaneous tumour or orthotopic transplanted models. The effect of MS4A4A blockade on the tumour immune microenvironment was assessed by flow cytometry and mass cytometry. RNA sequencing and western blot analysis were used to further explore the molecular mechanism by which MS4A4A promoted macrophages M2 polarisation. RESULTS: MS4A4A is selectively expressed by TAMs in different types of tumours, and was associated with adverse clinical outcome in patients with cancer. In vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment both curb tumour growth and improve the effect of ICI therapy. MS4A4A blockade treatment reshaped the tumour immune microenvironment, resulting in reducing the infiltration of M2-TAMs and exhausted T cells, and increasing the infiltration of effector CD8+ T cells. Anti-MS4A4A plus anti-programmed cell death protein 1 (PD-1) therapy remained effective in large, treatment-resistant tumours and could induce complete regression when further combined with radiotherapy. Mechanistically, MS4A4A promoted M2 polarisation of macrophages by activating PI3K/AKT pathway and JAK/STAT6 pathway. CONCLUSION: Targeting MS4A4A could enhance the ICI efficacy and represent a new anticancer immunotherapy.

Hexokinase 2 confers radio-resistance in hepatocellular carcinoma by promoting autophagy-dependent degradation of AIMP2.

With technological advancements, radiotherapy (RT) has become an effective non-surgical treatment for hepatocellular carcinoma (HCC), comprehensively improving the local control rate of patients with HCC. However, some patients with HCC still experience radio-resistance, cancer recurrence, and distant metastasis following RT. Our previous study has revealed that hexokinase 2 (HK2), a potent oncogene, was overexpressed in radio-resistant HCC cell lines; however, its role in HCC radio-resistance remains elusive. Here, we confirmed the upregulation of HK2 in HCC tissue, which is related to unfavorable prognosis in patients with HCC, and demonstrated that HK2 exerts a radio-resistant role by attenuating apoptosis and promoting proliferation in HCC cell lines. HK2 downregulation combined with ionizing radiation showed an excellent synergistic lethal effect. Mechanistically, HK2 alleviated ionizing radiation-mediated apoptosis by complexing with pro-apoptotic protein aminoacyl tRNA synthetase complex interacting multifunctional protein 2 (AIMP2) while enhancing its autophagic lysosomal-dependent degradation, thereby increasing radio-resistance of HCC. Pharmacologically, ketoconazole, an FDA-approved antifungal drug, served as an inhibitor of HK2 and synergistically enhanced the efficacy of RT. Our results indicated that HK2 played a vital role in radio-resistance and could be a potential therapeutic target for improving RT efficacy in HCC.

A comprehensive review of nano-delivery system for tea polyphenols: Construction, applications, and challenges.

Tea polyphenols (TPs) are important bioactive compounds in tea and have excellent physiological regulation functions. However, the extraction and purification of TPs are key technologies affecting their further application, and the chemical instability, poor bioavailability of TPs are major challenges for researchers. In the past decade, therefore, research and development of advanced carrier systems for the delivery of TPs has been greatly promoted to improve their poor stability and poor bioavailability. In this review, the properties and function of TPs are introduced, and the recent advances in the extraction and purification technologies are systematically summarized. Particularly, the intelligent delivery of TPs via novel nano-carriers is critically reviewed, and the application of TPs nano-delivery system in medical field and food industry is also described. Finally, the main limitations, current challenges and future perspectives are highlighted in order to provide research ideas for exploiting nano-delivery carriers and their application in TPs.

Layered Double Hydroxide@Metal-Organic Framework Hybrids for Extraction of Indole-3-Carbinol From Cruciferous Vegetables.

Cruciferous vegetables are rich in glucosinolates, which can be metabolized to produce the antitumor compound indole-3-carbinol (I3C). The conventional solvent extraction method for I3C is inefficient. To improve the extraction efficiency of I3C from cruciferous vegetables, we prepared a metal-organic framework (MOF) material (Fe3O4@Zn-Al-LDH@B-D-MIL-100). First, Fe3O4 nanoparticles were introduced to layered double hydroxides by in situ polymerization. Then, the MOF material was grown on the surface of the layered double hydroxide by co-precipitation and the layer-by-layer self-assembly method. This gave Fe3O4@Zn-Al-LDH@B-D-MIL-100, which was characterized using a variety of techniques. The results showed that Fe3O4@Zn-Al-LDH@B-D-MIL-100 had a double-layer porous structure, excellent superparamagnetism (11.54955 emu/g), a large specific surface area (174.04 m2/g), and a pore volume (0.26 cm3/g). The extraction conditions for I3C were optimized. Non-linear fitting of the static adsorption model showed that the adsorption was mainly monolayer. Fe3O4@Zn-Al-LDH@B-D-MIL-100 had fast adsorption kinetics and could extract 95% of I3C in 45 min. It is superior to the traditional solvent extraction method because of its high enrichment efficiency in a short time and environmental friendliness. The successful preparation of the new nanomaterial will provide a new reference for the enrichment and extraction of the I3C industry.

TXN inhibitor impedes radioresistance of colorectal cancer cells with decreased ALDH1L2 expression via TXN/NF-κB signaling pathway.

BACKGROUND: Colorectal cancer (CRC) is prevalent worldwide and is often challenged by treatment failure and recurrence due to resistance to radiotherapy. Here, we aimed to identify the elusive underlying molecular mechanisms of radioresistance in CRC. METHODS: Weighted gene co-expression network analysis was used to identify potential radiation-related genes. Colony formation and comet assays and multi-target single-hit survival and xenograft animal models were used to validate the results obtained from the bioinformatic analysis. Immunohistochemistry was performed to examine the clinical characteristics of ALDH1L2. Co-immunoprecipitation, immunofluorescence and flow cytometry were used to understand the molecular mechanisms underlying radioresistance. RESULTS: Bioinformatic analysis, in vitro, and in vivo experiments revealed that ALDH1L2 is a radiation-related gene, and a decrease in its expression induces radioresistance in CRC cells by inhibiting ROS-mediated apoptosis. Patients with low ALDH1L2 expression exhibit resistance to radiotherapy. Mechanistically, ALDH1L2 interacts with thioredoxin (TXN) and regulates the downstream NF-κB signaling pathway. PX-12, the TXN inhibitor, overcomes radioresistance due to decreased ALDH1L2. CONCLUSIONS: Our results provide valuable insights into the potential role of ALDH1L2 in CRC radiotherapy. We propose that the simultaneous application of TXN inhibitors and radiotherapy would significantly ameliorate the clinical outcomes of patients with CRC having low ALDH1L2.

Integration of glucose and cardiolipin anabolism confers radiation resistance of HCC.

BACKGROUND AND AIMS: Poor response to ionizing radiation (IR) due to resistance remains a clinical challenge. Altered metabolism represents a defining characteristic of nearly all types of cancers. However, how radioresistance is linked to metabolic reprogramming remains elusive in hepatocellular carcinoma (HCC). APPROACH AND RESULTS: Baseline radiation responsiveness of different HCC cells were identified and cells with acquired radio-resistance were generated. By performing proteomics, metabolomics, metabolic flux, and other functional studies, we depicted a metabolic phenotype that mediates radiation resistance in HCC, whereby increased glucose flux leads to glucose addiction in radioresistant HCC cells and a corresponding increase in glycerophospholipids biosynthesis to enhance the levels of cardiolipin. Accumulation of cardiolipin dampens the effectiveness of IR by inhibiting cytochrome c release to initiate apoptosis. Mechanistically, mammalian target of rapamycin complex 1 (mTORC1) signaling-mediated translational control of hypoxia inducible factor-1α (HIF-1α) and sterol regulatory element-binding protein-1 (SREBP1) remodels such metabolic cascade. Targeting mTORC1 or glucose to cardiolipin synthesis, in combination with IR, strongly diminishes tumor burden. Finally, activation of glucose metabolism predicts poor response to radiotherapy in cancer patients. CONCLUSIONS: We demonstrate a link between radiation resistance and metabolic integration and suggest that metabolically dismantling the radioresistant features of tumors may provide potential combination approaches for radiotherapy in HCC.

Development of a Joint Prediction Model Based on Both the Radiomics and Clinical Factors for Predicting the Tumor Response to Neoadjuvant Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer.

PURPOSE: Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for locally advanced rectal cancer (LARC). However, the accuracy of traditional clinical indicators in predicting tumor response is poor. Recently, radiomics based on magnetic resonance imaging (MRI) has been regarded as a promising noninvasive assessment method. The present study was conducted to develop a model to predict the pathological response by analyzing the quantitative features of MRI and clinical risk factors, which might predict the therapeutic effects in patients with LARC as accurately as possible before treatment. PATIENTS AND METHODS: A total of 82 patients with LARC were enrolled as the training cohort and internal validation cohort. The pre-CRT MRI after pretreatment was acquired to extract texture features, which was finally selected through the minimum redundancy maximum relevance (mRMR) algorithm. A support vector machine (SVM) was used as a classifier to classify different tumor responses. A joint radiomics model combined with clinical risk factors was then developed and evaluated by receiver operating characteristic (ROC) curves. External validation was performed with 107 patients from another center to evaluate the applicability of the model. RESULTS: Twenty top image texture features were extracted from 6192 extracted-radiomic features. The radiomics model based on high-spatial-resolution T2-weighted imaging (HR-T2WI) and contrast-enhanced T1-weighted imaging (T1+C) demonstrated an area under the curve (AUC) of 0.8910 (0.8114-0.9706) and 0.8938 (0.8084-0.9792), respectively. The AUC value rose to 0.9371 (0.8751-0.9997) and 0.9113 (0.8449-0.9776), respectively, when the circumferential resection margin (CRM) and carbohydrate antigen 19-9 (CA19-9) levels were incorporated. Clinical usefulness was confirmed in an external validation cohort as well (AUC, 0.6413 and 0.6818). CONCLUSION: Our study indicated that the joint radiomics prediction model combined with clinical risk factors showed good predictive ability regarding the treatment response of tumors as accurately as possible before treatment.

Alterations of the Gut Microbiome Composition and Lipid Metabolic Profile in Radiation Enteritis.

Radiation enteritis (RE) is a common complication in cancer patients receiving radiotherapy. Although studies have shown the changes of this disease at clinical, pathological and other levels, the dynamic characteristics of local microbiome and metabolomics are hitherto unknown. We aimed to examine the multi-omics features of the gut microecosystem, determining the functional correlation between microbiome and lipid metabolites during RE activity. By delivering single high-dose irradiation, a RE mouse model was established. High-throughput 16S rDNA sequencing and global lipidomics analysis were performed to examine microbial and lipidomic profile changes in the gut microecosystem. Spearman correlation analysis was used to determine the functional correlation between bacteria and metabolites. Clinical samples were collected to validate the above observations. During RE activity, the intestinal inflammation of the mice was confirmed by typical signs, symptoms, imaging findings and pathological evidences. 16S datasets revealed that localized irradiation dramatically altered the gut microbial composition, resulting in a decrease ratio of Bacteroidetes to Firmicutes. Lipidomics analysis indicated the remarkable lipidomic profile changes in enteric epithelial barrier, determining that glycerophospholipids metabolism was correlated to RE progression with the highest relevance. Spearman correlation analysis identified that five bacteria-metabolite pairs showed the most significant functional correlation in RE, including Alistipes-PC(36:0e), Bacteroides-DG(18:0/20:4), Dubosiella-PC(35:2), Eggerthellaceae-PC(35:6), and Escherichia-Shigella-TG(18:2/18:2/20:4). These observations were partly confirmed in human specimens. Our study provided a comprehensive description of microbiota dysbiosis and lipid metabolic disorders in RE, suggesting strategies to change local microecosystem to relieve radiation injury and maintain homeostasis.

Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer.

PURPOSE: Although tumor mutation burden (TMB) has been well known to predict the response to immune checkpoint inhibitors (ICI), lack of randomized clinical trial data has restricted its clinical application. This study aimed to explore the significance and feasibility of biomarker combination based on TMB and copy-number alteration (CNA) for the prognosis of each tumor and prediction for ICI therapy in metastatic pan-cancer milieu. EXPERIMENTAL DESIGN: Non-ICI-treated MSK pan-cancer cohort was used for prognosis analysis. Three independent immunotherapy cohorts, including non-small cell lung cancer (n = 240), skin cutaneous melanoma (n = 174), and mixed cancer (Dana-Farber, n = 98) patients from previous studies, were analyzed for efficacy of ICI therapy. RESULTS: TMB and CNA showed optimized combination for the prognosis of most metastatic cancer types, and patients with TMBlowCNAlow showed better survival. In the predictive analysis, both TMB and CNA were independent predictive factors for ICI therapy. Remarkably, when TMB and CNA were jointly analyzed, those with TMBhighCNAlow showed favorable responses to ICI therapy. Meanwhile, TMBhighCNAlow as a new biomarker showed better prediction for ICI efficacy compared with either TMB-high or CNA-low alone. Furthermore, analysis of the non-ICI-treated MSK pan-cancer cohort supported that the joint stratification of TMB and CNA can be used to categorize tumors into distinct sensitivity to ICI therapy across pan-tumors. CONCLUSIONS: The combination of TMB and CNA can jointly stratify multiple metastatic tumors into groups with different prognosis and heterogeneous clinical responses to ICI treatment. Patients with TMBhighCNAlow cancer can be an optimal subgroup for ICI therapy.

A meta-analysis of weekly cisplatin versus three weekly cisplatin chemotherapy plus concurrent radiotherapy (CRT) for advanced head and neck cancer (HNC).

PURPOSE: This study was performed to compare the efficacies and acute toxicities in weekly- and three weekly- cisplatin based concurrent chemoradiotherapy (CCRT) for advanced HNC patients. RESULTS: 779 patients of 10 studies were eligible. No difference in the 2-, 3-year OS or 1-, 2-year LRFS was observed, whereas patients in three weekly CCRT arm tended to have a better 5-year OS (HR=1.79, 95%C 0.97-3.31, p=0.06). Weekly arm seemed to show less gastrointestinal toxicities (RR=0.59, 95%CI 0.34-1.02, p=0.06), but similar hematologic toxicity compared to three weekly arm. Subgroup analysis displayed more grade ≥3 mucositis (RR=1.72, p=0.01), and more chemotherapy related delay/interrupt (RR=2.68, p<0.0001) in weekly arm for non-nasopharynx carcinoma (non-NPC) HNC. METHODS: We conducted the meta-analysis by searching PubMed, MEDLINE, ScienceDirect, Cochrane Library and China National Knowledge Infrastructure (CNKI) databases. The primary endpoint was overall survival (OS) with secondary endpoints locoregional recurrence-free survival (LRFS) and grade≥3 acute adverse events. RevMan 5.2 was used to perform statistical analyses. CONCLUSIONS: Three weekly cisplatin-based CCRT might achieve a higher long-term OS with no significant difference in a shorter OS and LRFS. Weekly arm was associated with less gastrointestinal toxicities but more grade≥3 mucositis and chemotherapy related delay/interrupt. Large randomized trials were urgent to further define superiority of these two regimens.

A meta-analysis comparing cisplatin-based to carboplatin-based chemotherapy in moderate to advanced squamous cell carcinoma of head and neck (SCCHN).

PURPOSE: This study was performed to compare the efficacies and toxicities of cisplatin (CDDP)- and carboplatin (CBDCA)-based chemotherapy (CT) in patients with SCCHN. METHODS: The search strategy included Pubmed, Science Direct, the Cochrane Library, and the China National Knowledge Internet Web. Statistical analyses were performed using RevMan 5.2. The primary endpoint was overall survival (OS) with secondary endpoints of locoregional control (LRC) and grade ≥ 3 toxicity. RESULTS: Overall, 12 studies and 1165 patients were included. CDDP-based CT significantly improved 5-year OS (HR=0.67, 95% CI, 0.49 to 0.91; P=0.01) compared to the CBDCA group. No difference in the 3-year OS/LRC was observed, but a subgroup analysis showed a better 3-year OS in the CDDP arm for non-nasopharynx carcinoma (non-NPC) SCCHN (HR=0.66, 95% CI, 0.48 to 0.91; P=0.01). The CDDP-based CT was associated with more gastrointestinal toxicities (RR=4.58; P=0.005) and nephrotoxicity (4/110=3.6%) compared to the CBDCA group, but fewer anemia, leukopenia and thrombocytopenia with RRs of 0.27, 0.71, and 0.28 respectively. CONCLUSIONS: Patients with CDDP-based CT can achieve a higher OS, but there is no significant difference in LRC. The CDDP-based CT is associated with fewer hematological toxicities but more gastrointestinal toxicities and nephrotoxicity compared to the CBDCA arm.

The MDM2 309 T/G polymorphism is associated with head and neck cancer risk especially in nasopharyngeal cancer: a meta-analysis.

BACKGROUND: Published data on the association between mouse double minute 2 (MDM2) 309 T/G single nucleotide polymorphism (SNP) and head and neck cancer (HNC) risk are inconclusive. To derive a more precise estimation of the relationship, we performed a meta-analysis. MATERIAL AND METHODS: A systematic computerized search of PubMed was performed. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association between the polymorphism and HNC risk. The pooled ORs were performed for TT versus GG, TG versus GG, dominant model (TT+TG vs. GG) and recessive model (TT vs. TG+GG), respectively. RESULTS: A total of 9 studies including 2,755 cases and 4,121 controls were involved in the final meta-analysis. The results of the overall meta-analysis provided some evidence of an association between the polymorphism and HNC risk (OR = 0.82, 95% CI 0.67-0.99 for TG vs. GG). In the subgroup meta-analysis based on the types of tumor, we detected a significantly decreased NPC risk for all genetic models. CONCLUSION: This meta-analysis suggests that the GG genotype of MDM2 SNP309 is associated with HNC risk. The MDM2 SNP309G allele is a highly penetrant risk factor for developing NPC.

[Effect of gemcitabine in enhancing the radiosensitivity of HepG2 hepatoma cells and the possible mechanism].

OBJECTIVE: To evaluate the effect of gemcitabine in enhancing the radiosensitivity of hepatoma cell line HepG2 and explore its mechanisms. METHODS: Clonogenic survival assay is employed to calculate the ratios of L-Q model radiation biology parameters and radiosensitization after different doses of irradiation. Flow cytometry was used to detect the changes in HepG2 cell cycle and apoptosis rate after gemcitabine treatment and radiation exposure. RESULTS: The survival fraction at 2 Gy of HepG2 cells treated with gemcitabine was significantly lower, and the value of alpha was significantly higher than those of untreated cells. GEM treatment increased the percentage of radiation-induced G0/G1 phase cells and cell apoptosis. CONCLUSION: Gemcitabine can significantly enhance the radiosensitivity of HepG2 cells by enhancing radiation-induced cell cycle arrest in G0/G1 phase and cell apoptosis.

Radiation-inducible PTEN expression radiosensitises hepatocellular carcinoma cells.

PURPOSE: To test the radiosensitising effects of a tumour-suppressor gene, phosphatase and tensin homologue deleted from chromosome 10 (PTEN), in hepatocellular carcinoma cells (HCC). MATERIALS AND METHODS: Radiation-induced wild-type PTEN or mutant PTEN was transfected into the SMMC-7721 human hepatocellular carcinoma cells. The expressions of PTEN and serine/threonine protein kinase (Akt) were detected by Western blot analysis. 3-(4,5)-dimethylthiahiazo-(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) absorbance and clonogenic survival assays were used to determine cell viability, proliferation and radiosensitivity. By performing cell-cycle analysis, terminal deoxynucleotidyltransferase (TdT)-mediated dUTP biotin nick end labelling (TUNEL) assays and gamma-histone H2A (γ-H2AX) formation assays, we were able to explore the mechanism of PTEN enhancement of radiosensitivity. RESULTS: Restoration of wild-type PTEN induced growth suppression and sensitised the cells to ionising radiation specifically by its lipid phosphatase activity through the PTEN-phosphatidylinositol 3-kinase (PI3K)-Akt signalling pathway. Restoring PTEN function correlated with G2/M arrest, apoptosis and the retardation of repair of radiation-induced double strand breaks (DSB). CONCLUSIONS: Our study suggests that strategies designed to restore the expression of PTEN may represent promising new therapies for sensitising HCC cells to ionising radiation.