Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells.

Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of CD8+ T cells. Tumor cells outcompete CD8+ T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction, thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8+ T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of cancer therapies.

N6-methyladenosine reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer.

BACKGROUND: Chemoresistance is a major cause of treatment failure in gastric cancer (GC). Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an N6-methyladenosine (m6A)-binding protein involved in a variety of cancers. However, whether m6A modification and hnRNPA2B1 play a role in GC chemoresistance is largely unknown. In this study, we aimed to investigate the role of hnRNPA2B1 and the downstream mechanism in GC chemoresistance. METHODS: The expression of hnRNPA2B1 among public datasets were analyzed and validated by quantitative PCR (qPCR), Western blotting, immunofluorescence, and immunohistochemical staining. The biological functions of hnRNPA2B1 in GC chemoresistance were investigated both in vitro and in vivo. RNA sequencing, methylated RNA immunoprecipitation, RNA immunoprecipitation, and RNA stability assay were performed to assess the association between hnRNPA2B1 and the binding RNA. The role of hnRNPA2B1 in maintenance of GC stemness was evaluated by bioinformatic analysis, qPCR, Western blotting, immunofluorescence, and sphere formation assays. The expression patterns of hnRNPA2B1 and downstream regulators in GC specimens from patients who received adjuvant chemotherapy were analyzed by RNAscope and multiplex immunohistochemistry. RESULTS: Elevated expression of hnRNPA2B1 was found in GC cells and tissues, especially in multidrug-resistant (MDR) GC cell lines. The expression of hnRNPA2B1 was associated with poor outcomes of GC patients, especially in those who received 5-fluorouracil treatment. Silencing hnRNPA2B1 effectively sensitized GC cells to chemotherapy by inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo. Mechanically, hnRNPA2B1 interacted with and stabilized long noncoding RNA NEAT1 in an m6A-dependent manner. Furthermore, hnRNPA2B1 and NEAT1 worked together to enhance the stemness properties of GC cells via Wnt/ß-catenin signaling pathway. In clinical specimens from GC patients subjected to chemotherapy, the expression levels of hnRNPA2B1, NEAT1, CD133, and CD44 were markedly elevated in non-responders compared with responders. CONCLUSION: Our findings indicated that hnRNPA2B1 interacts with and stabilizes lncRNA NEAT1, which contribute to the maintenance of stemness property via Wnt/ß-catenin pathway and exacerbate chemoresistance in GC.

The impact of the digital economy on creative industries development: Empirical evidence based on the China.

Digital economy has become a "new engine" that driving global economic growth. Nevertheless, numerous controversies persist regarding whether and how digital economy can facilitate the development of emerging industries. Thus, this paper investigates how digital economy affects creative industries development in China and whether innovation efficiency mediates this relationship. Drawing upon a panel data set containing 29 Chinese provinces from 2012 to 2019, an econometric model is constructed for empirical analysis. We find that digital economy significantly promotes creative industries development, and innovation efficiency plays a partial mediating role between digital economy and creative industries development. According to the influence mechanism, the digital economy of various regions could promote the creative industries development by improving the innovation efficiency. Finally, relevant suggestions were put forward from the expanding application paths, improving regional innovation efficiency, and creating an innovative environment.

Mitochondria-targeted photodynamic therapy triggers GSDME-mediated pyroptosis and sensitizes anti-PD-1 therapy in colorectal cancer.

BACKGROUND: The effectiveness of immune checkpoint inhibitors in colorectal cancer (CRC) is limited due to the low tumor neoantigen load and low immune infiltration in most microsatellite-stable (MSS) tumors. This study aimed to develop a mitochondria-targeted photodynamic therapy (PDT) approach to provoke host antitumor immunity of MSS-CRC and elucidate the underlying molecular mechanisms. METHODS: The role and mechanism of mitochondria-targeted PDT in inhibiting CRC progression and inducing pyroptosis were evaluated both in vitro and in vivo. The immune effects of PDT sensitization on PD-1 blockade were also assessed in CT26 and 4T1 tumor-bearing mouse models. RESULTS: Here, we report that PDT using IR700DX-6T, a photosensitizer targeting the mitochondrial translocation protein, may trigger an antitumor immune response initiated by pyroptosis in CRC. Mechanistically, IR700DX-6T-PDT produced reactive oxygen species on light irradiation and promoted downstream p38 phosphorylation and active caspase3 (CASP3)-mediated cleavage of gasdermin E (GSDME), subsequently inducing pyroptosis. Furthermore, IR700DX-6T-PDT enhanced the sensitivity of MSS-CRC cells to PD-1 blockade. Decitabine, a demethylation drug used to treat hematologic neoplasms, disrupted the abnormal methylation pattern of GSDME in tumor cells, enhanced the efficacy of IR700DX-6T-PDT, and elicited a potent antitumor immune response in combination with PD-1 blockade and IR700DX-6T-PDT. CONCLUSION: Our work provides clear a understanding of immunogenic cell death triggered by mitochondria-targeted PDT, offering a new approach for enhancing the efficacy of PD-1 blockade in CRC.

Microbubbles activated by low-frequency ultrasound enhance the anti-tumor effects of curcumin in glioma cells by suppressing the TGF-ß1/Smad/VEGF/NCAM signaling pathway.

This study investigated whether microbubbles activated by low-frequency ultrasound enhanced the anti-tumor effects of curcumin in glioma cells. CCK8 proliferation assay, scratch migration assay, and transwell invasion assay were performed to estimate the proliferation, migration, and invasion rates of the glioma cells in blank control and different treatment groups, respectively. Quantitative RT-PCR (qRT-PCR) analysis was performed to determine the relative expression levels of VEGF and NCAM mRNAs in the various experimental groups. Western blotting was performed to determine the activity status of the TGF-ß1/Smad signaling pathway in various groups of glioma cells by estimating the expression levels of p-SMAD2/3, VEGF, and NCAM proteins. Combined treatment (Cur-Us-MBs) with microbubbles activated by low-frequency ultrasound and curcumin significantly reduced the in vitro proliferation, migration, and invasiveness of glioma cells compared to the control and other treatment groups. Furthermore, Cur-Us-MBs significantly reduced the expression levels of VEGF and NCAM mRNAs and proteins and p-Smad2/3 proteins , including those cells stimulated with rhTGF-ß. These suggested that microbubbles activated by low-frequency ultrasound enhanced the inhibition of TGF-ß1/Smad/VEGF/NCAM signaling pathway by curcumin，and enhanced the antitumor effects of curcumin by significantly reducing in vitro proliferation, migration, and invasiveness of glioma cells through this pathway.

Reprogramming and multi-lineage transdifferentiation attenuate the tumorigenicity of colorectal cancer cells.

Significant advances have been made in reprogramming various somatic cells into induced pluripotent stem cells (iPSCs) and in multi-lineage differentiation (transdifferentiation) into different tissues. These manipulable transdifferentiating techniques may be applied in cancer therapy. Limited works have been reported that cancer cell malignancy can be switched to benign phenotypes through reprogramming techniques. Here, we reported that two colorectal cancer (CRC) cell lines (DLD1, HT29) could be reprogrammed into iPSCs (D-iPSCs, H-iPSCs). D- and H-iPSCs showed reduced tumorigenesis. Furthermore, we successfully induced D- and H-iPSCs differentiation into terminally differentiated cell types such as cardiomyocyte, neuron, and adipocyte-like cells. Impressively, the differentiated cells exhibited further attenuated tumorigenesis in vitro and in vivo. RNA-Seq further indicated that epigenetic changes occurred after reprogramming and transdifferentiation that caused reduced tumorigenicity. Overall, our study indicated that CRC cells can be reprogrammed and further differentiated into terminally differentiated lineages with attenuation of their malignancy in vitro and in vivo. The current work sheds light on a potential multi-lineage differentiation therapeutic strategy for colorectal cancer.

The effect of nutritional biochemical indexes on the hospitalization outcome of COVID-19.

Aims to investigate the relationship between nutritional biochemical indexes and hospitalization outcomes of COVID-19 patients, 132 continuous patients with COVID-19 from December 2022 to January 2023 in Lishui hospital were retrospectively analyzed, and the nutritional biochemical indexes in peripheral blood, such as total protein, albumin, calcium, phosphorus, and magnesium, were detected. Meanwhile, the levels of several cytokines and PBMC subtypes (CD4, CD3, CD8, NK and B cells) were detected too. The Spearman correlation analysis, one-way ANOVA and multivariate logit regression were conducted. Results suggested that the levels of total protein and albumin were significantly decreased in patients with poor outcomes, and the levels of calcium, phosphorus, and magnesium were significantly correlated with hospitalization outcomes. COVID-19 patients with diabetes had higher levels of IL-6 and IFN-γ than those patients without diabetes. The levels of IL-2, IFN-γ, IL-6 and Il-10 in the dead patients were significantly higher than those in the recovery and worse patients. Total protein and albumin were significantly positively correlated with levels of NK and B, CD4, CD8, CD3 lymphocytes. The levels of CD4, CD8 and CD3 lymphocytes were significantly decreased in dead patients than other patients. Multivariate logit regression analysis suggests that lymphocyte number, albumin and IL-6 are independent risk factors to evaluate the hospitalization outcome. In summary, nutritional biochemical indexes were significantly corelated with cytokines and PBMC subsets, and had an impact on the severity of COVID-19 patients. Improvement of low protein malnutrition is broad-spectrum and basic strategy to improve the hospitalization outcome of COVID-19.

Identification of Crocetin as a Dual Agonist of GPR40 and GPR120 Responsible for the Antidiabetic Effect of Saffron.

Crocin, a glycoside of crocetin, has been known as the principal component responsible for saffron's antidiabetic, anticancer, and anti-inflammatory effects. Crocetin, originating from the hydrolytic cleavage of crocin in biological systems, was subjected to ligand-based virtual screening in this investigation. Subsequent biochemical analysis unveiled crocetin, not crocin, as a novel dual GPR40 and GPR120 agonist, demonstrating a marked preference for GPR40 and GPR120 over peroxisome proliferator-activated receptors (PPAR)γ. This compound notably enhanced insulin and GLP-1 secretion from pancreatic ß-cells and intestinal neuroendocrine cells, respectively, presenting a dual mechanism of action in glucose-lowering effects. Docking simulations showed that crocetin emulates the binding characteristics of natural ligands through hydrogen bonds and hydrophobic interactions, whereas crocin's hindered fit within the binding pocket is attributed to steric constraints. Collectively, for the first time, this study unveils crocetin as the true active component of saffron, functioning as a GPR40/120 agonist with potential implications in antidiabetic interventions.

The lncRNA MIR99AHG directs alternative splicing of SMARCA1 by PTBP1 to enable invadopodia formation in colorectal cancer cells.

Alternative splicing regulates gene expression and functional diversity and is often dysregulated in human cancers. Here, we discovered that the long noncoding RNA (lncRNA) MIR99AHG regulated alternative splicing to alter the activity of a chromatin remodeler and promote metastatic behaviors in colorectal cancer (CRC). MIR99AHG was abundant in invasive CRC cells and metastatic tumors from patients and promoted motility and invasion in cultured CRC cells. MIR99AHG bound to and stabilized the RNA splicing factor PTBP1, and this complex increased cassette exon inclusion in the mRNA encoding the chromatin remodeling gene SMARCA1. Specifically, MIR99AHG altered the nature of PTBP1 binding to the splice sites on intron 12 of SMARCA1 pre-mRNA, thereby triggering a splicing switch from skipping to including exon 13 to produce the long isoform, SMARCA1-L. SMARCA1, but not SMARCA1-L, suppressed invadopodia formation, cell migration, and invasion. Analysis of CRC samples revealed that the abundance of MIR99AHG transcript positively correlated with that of SMARCA1-L mRNA and PTBP1 protein and with poor prognosis in patients with CRC. Furthermore, TGF-ß1 secretion from cancer-associated fibroblasts increased MIR99AHG expression in CRC cells. Our findings identify an lncRNA that is induced by cues from the tumor microenvironment and that interacts with PTBP1 to regulate alternative splicing, potentially providing a therapeutic target and predictive biomarker for metastatic CRC.

Association of CDX2 and mucin expression with chemotherapeutic benefits in patients with stage II/III gastric cancer.

BACKGROUND: Better predictors of patients with stage II/III gastric cancer (GC) most likely to benefit from adjuvant chemotherapy are urgently needed. This study aimed to assess the ability of CDX2 and mucin markers to predict prognosis and fluorouracil-based adjuvant chemotherapy benefits. METHODS: CDX2 and mucin protein expressions were examined by immunohistochemistry and compared with survival and adjuvant chemotherapy benefits in a prospective evaluation cohort of 782 stage II/III GC patients. Then, the main findings were validated in an independent validation cohort (n = 386) and an external mRNA sequencing dataset (ACRG cohort, n = 193). RESULTS: In the evaluation cohort, CDX2, CD10, MUC2, MUC5AC, and MUC6 expressions were observed in 59.7%, 26.7%, 27.6%, 55.1%, and 57.7% of patients, respectively. However, only the expression of CDX2 was found to be associated with adjuvant chemotherapy benefits. Most importantly, CDX2-negative patients had a poorer prognosis when treated with surgery only, while the prognosis of CDX2-negative and CDX2-positive patients was similar when receiving postoperative adjuvant chemotherapy. Further analysis revealed that patients with CDX2 negative tumors benefited from chemotherapy (5-year overall survival rates: 60.0% with chemotherapy vs. 23.2% with surgery-only, p < 0.001), whereas patients with CDX2 positive tumors did not (pinteraction = 0.004). Consistent results were obtained in the validation and ACRG cohorts. CONCLUSIONS: Negative expression of CDX2 is an independent risk factor for survival in stage II/III GC, but subsequent adjuvant chemotherapy is able to compensate for this unfavorable effect. Therefore, active chemotherapy is more urgent for patients with negative CDX2 expression than for patients with positive CDX2 expression.

WNT2-SOX4 positive feedback loop promotes chemoresistance and tumorigenesis by inducing stem-cell like properties in gastric cancer.

Gastric cancer (GC) is characterized by its vigorous chemoresistance to current therapies, which is attributed to the highly heterogeneous and immature phenotype of cancer stem cells (CSCs) during tumor initiation and progression. The secretory WNT2 ligand regulates multiple cancer pathways and has been demonstrated to be a potential therapeutic target for gastrointestinal tumors; however, its role involved in gastric CSCs (GCSCs) remains unclear. Here, we found that overexpression of WNT2 enhanced stemness properties to promote chemoresistance and tumorigenicity in GCSCs. Mechanistically, WNT2 was positively regulated by its transcription factor SOX4, and in turn, SOX4 was upregulated by the canonical WNT2/FZD8/ß-catenin signaling pathway to form an auto-regulatory positive feedback loop, resulting in the maintenance of GCSCs self-renewal and tumorigenicity. Furthermore, simultaneous overexpression of both WNT2 and SOX4 was correlated with poor survival and reduced responsiveness to chemotherapy in clinical GC specimens. Blocking WNT2 using a specific monoclonal antibody significantly disrupted the WNT2-SOX4 positive feedback loop in GCSCs and enhanced the chemotherapeutic efficacy when synergized with the chemo-drugs 5-fluorouracil and oxaliplatin in a GCSC-derived mouse xenograft model. Overall, this study identified a novel WNT2-SOX4 positive feedback loop as a mechanism for GCSCs-induced chemo-drugs resistance and suggested that the WNT2-SOX4 axis may be a potential therapeutic target for gastric cancer treatment.

Modelling the effects of topographic heterogeneity on distribution of Nitraria tangutorum Bobr. species in deserts using LiDAR-data.

Microclimate ecology is attracting renewed attention because of its fundamental importance in understanding how organisms respond to climate change. Many hot issues can be investigated in desert ecosystems, including the relationship between species distribution and environmental gradients (e.g., elevation, slope, topographic convergence index, and solar insolation). Species Distribution Models (SDMs) can be used to understand these relationships. We used data acquired from the important desert plant Nitraria tangutorum Bobr. communities and desert topographic factors extracted from LiDAR (Light Detection and Ranging) data of one square kilometer in the inner Mongolia region of China to develop SDMs. We evaluated the performance of SDMs developed with a variety of both the parametric and nonparametric algorithms (Bioclimatic Modelling (BIOCLIM), Domain, Mahalanobi, Generalized Linear Model, Generalized Additive Model, Random Forest (RF), and Support Vector Machine). The area under the receiver operating characteristic curve was used to evaluate these algorithms. The SDMs developed with RF showed the best performance based on the area under curve (0.7733). We also produced the Nitraria tangutorum Bobr. distribution maps with the best SDM and suitable habitat area of the Domain model. Based on the suitability map, we conclude that Nitraria tangutorum Bobr. is more suited to southern part with 0-20 degree slopes at an elevation of approximately 1010 m. This is the first attempt of modelling the effects of topographic heterogeneity on the desert species distribution on a small scale. The presented SDMs can have important applications for predicting species distribution and will be useful for preparing conservation and management strategies for desert ecosystems on a small scale.

Regulatory role of exosomes in colorectal cancer progression and potential as biomarkers.

Colorectal cancer (CRC) remains an enormous challenge to human health worldwide. Unfortunately, the mechanism underlying CRC progression is not well understood. Mounting evidence has confirmed that exosomes play a vital role in CRC progression, which has attracted extensive attention among researchers. In addition to acting as messengers between CRC cells, exosomes also participate in the CRC immunomodulatory process and reshape immune function. As stable message carriers and liquid biopsy option under development, exosomes are promising biomarkers in the diagnosis or treatment of CRC. In this review we have described and analyzed the biogenesis and release of exosomes and current research on the role of exosomes in immune regulation and metastasis of CRC. Moreover, we have discussed candidate exosomal molecules as potential biomarkers to diagnose CRC, predict CRC progression, or determine CRC chemoresistance, and described the significance of exosomes in the immunotherapy of CRC. This review provides insight to further understand the role of exosomes in CRC progression and identify valuable biomarkers that facilitate the clinical management of CRC patients.

7-hydroxycoumarin-ß-D-glucuronide protects against cisplatin-induced acute kidney injury via inhibiting p38 MAPK-mediated apoptosis in mice.

AIMS: Cisplatin is a widely-used drug in the clinical treatment of tumors, but kidney nephrotoxicity is one of the reasons that limits its widespread use. We previously found that 7-hydroxycoumarin-ß-D-glucuronide (7-HCG) was one of metabolites of skimmin and highly enriched in the kidneys and maintained a high blood concentration in skimmin-treated rats. Therefore, we investigated whether 7-HCG has a protective effect on cisplatin-induced acute kidney injury. MATERIALS AND METHODS: Male C57BL/6 mice were continuously administered 7-HCG for five days, and on the third day, an intraperitoneal injection of cisplatin was given to induce acute kidney injury. After 72 h, the mice were sacrificed for analysis. Serum and renal tissue were collected for renal function evaluation. RNA sequencing was used to explore mechanism, and further validated by western blot and immunohistochemistry. In addition, pharmacokinetic study of oral 7-HCG administration was performed to examine how much 7-hydroxycoumarin (7-HC) was metabolized and 7-HC possible effect on renal protection. KEY FINDINGS: 7-HCG significantly reduced serum BUN and SCR levels, and alleviated pathological damage in renal tissue, and reduced the renal index. RNA sequencing revealed that 7-HCG could reverse p38 MAPK regulation and apoptosis. By western blotting, it was found that 7-HCG could reduce renal injury by reducing p-p38, p-ERK, p-JNK, cleaved-caspase3 and Bax. The immunohistochemical results of cleaved-caspase3 were consistent with western blotting. 7-HCG also significantly reduced the production of ROS in kidney tissue. Pharmacokinetic experiments have shown that 7-HCG in the blood increased rapidly and was eliminated slowly, with an average t1/2ß of 18.3 h. And the concentration of 7-HCG in the target organ kidney was about 4 times higher than that in blood. SIGNIFICANCE: Our findings indicate that 7-HCG could exert its protective effect against cisplatin-induced acute kidney injury by inhibiting apoptosis via p38 MAPK regulation and elucidates its pharmacokinetics.

Redox Dysregulation in the Tumor Microenvironment Contributes to Cancer Metastasis.

Significance: Redox dysregulation under pathological conditions results in excessive reactive oxygen species (ROS) accumulation, leading to oxidative stress and cellular oxidative damage. ROS function as a double-edged sword to modulate various types of cancer development and survival. Recent Advances: Emerging evidence has underlined that ROS impact the behavior of both cancer cells and tumor-associated stromal cells in the tumor microenvironment (TME), and these cells have developed complex systems to adapt to high ROS environments during cancer progression. Critical Issues: In this review, we integrated current progress regarding the impact of ROS on cancer cells and tumor-associated stromal cells in the TME and summarized how ROS production influences cancer cell behaviors. Then, we summarized the distinct effects of ROS during different stages of tumor metastasis. Finally, we discussed potential therapeutic strategies for modulating ROS for the treatment of cancer metastasis. Future Directions: Targeting the ROS regulation during cancer metastasis will provide important insights into the design of effective single or combinatorial cancer therapeutic strategies. Well-designed preclinical studies and clinical trials are urgently needed to understand the complex regulatory systems of ROS in the TME. Antioxid. Redox Signal. 39, 472-490.

Continuous-flow membrane bioreactor enhances enrichment and culture of autotrophic nitrifying bacteria by removing extracellular free organic carbon.

An activated sludge system can be inoculated with enriched nitrifying bacteria to enhance NH4+-N removal, or enriched nitrifying bacteria can be added directly to a river to remove NH4+-N. However, the enrichment culture is still generally inefficient and the technical bottleneck has not been clarified. Previous studies have shown that extracellular free organic carbon (EFOC) inhibits the growth of some autotrophic bacteria, and separating EFOC during culture with a membrane bioreactor (MBR) promotes the continuous growth of autotrophic bacteria and CO2 fixation. However, whether a membrane bioreactor can also be used to enrich and culture autotrophic nitrifying bacteria by separating EFOC has not been verified. In this study, an MBR was constructed to separate EFOC during the culture of nitrifying bacteria in activated sludge to confirm that the MBR better enriches and cultures nitrifying bacteria than a sequencing batch reactor (SBR). Our results showed that after culture for 34 days, the rate of NH4+-N removal and the nitrification rate by nitrifying bacteria in the MBR were 2.20-fold and 1.42-fold higher than in the SBR, respectively. The abundance of Nitrospira in the MBR was also 7.23-fold greater than in the SBR at the end of the experimental period. After 34 days, the average concentration of EFOC and the average EFOC/bacterial organic carbon ratio in the MBR were only 53% and 37% of those in the SBR, respectively. A correlation analysis suggested that the timely removal by the MBR of the EFOC generated during the culture process may be an important factor in promoting the growth of autotrophic nitrifying bacteria. The possible mechanism by which the MBR separates EFOC to the growth of promote autotrophic nitrifying bacteria is discussed from the perspective of the inhibitory effect of EFOC on cbb gene transcription. Our experimental results suggest a new approach to enhancing the enrichment of autotrophic nitrifying bacteria and extending the application of MBRs.

eEF1A1 promotes colorectal cancer progression and predicts poor prognosis of patients.

Colorectal cancer (CRC) is a major leading cause of cancer mortality worldwide in which dysregulated protein synthesis plays an etiologic role. The eukaryotic elongation factor 1 A1 (eEF1A1) exerts significant effects on protein synthesis by contributing to peptide chain extension. Whereas its role in CRC remains to be investigated. In this study, we found that the mRNA and protein levels of eEF1A1 were significantly upregulated in CRC cell lines and tissues. Elevated expression of eEF1A1 was correlated with shorter overall survival in 94 CRC patients. The inhibition of proliferation and cell cycle block were observed in CRC cells after eEF1A1 downregulation. Mechanistically, weighted gene correlation network analysis and further Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that mitogen-activated protein kinases (MAPKs) signaling pathways were significantly enriched in high-eEF1A1 expression group, and the levels of phosphorylated p38/JNK/ERK MAPK were dramatically decreased after eEF1A1 downregulation. Overexpression of eEF1A1 in CRC correlated with a poor prognosis. Collectively, this study determined the oncogenic role of eEF1A1 in CRC proliferation and tumorigenesis. eEF1A1 might be a promising therapeutic target and prognostic biomarker in CRC.

[N6-methyladenosine (m6A) binding protein hnRNPA2B1 is highly expressed in a variety of tumors and regulates tumor immune microenvironment].

Objective To investigate the expression of N6-methyladenosine (m6A) binding protein hnRNPA2B1 in various tumors and its relationship with prognosis and immune infiltration. Methods We investigated the expression of hnRNPA2B1 in different tumors and verified it in gastric cancer (GC) tissue microarray using immunohistochemistry. Univariate COX regression and Kaplan-Meier survival analysis were used to identify the prognostic value of hnRNPA2B1 in pan-cancer. In addition, we explored the correlation between the expression of hnRNPA2B1 and immune cell infiltration, immune checkpoint genes, tumor mutational burden (TMB) as well as microsatellite instability (MSI). Results The expression of hnRNPA2B1 was higher in tumor tissues than in corresponding normal tissues in most cancers. In GC tissue microarray, the expression of hnRNPA2B1 in GC tissues was significantly higher than that in paired adjacent normal tissues. High expression of hnRNPA2B1 was significantly associated with poor prognosis in 7 types of tumors. Moreover, the expression of hnRNPA2B1 was positively correlated with immune cell infiltration in a variety of tumors. In addition, hnRNPA2B1 was notably associated with immune checkpoint related genes, TMB and MSI. Conclusion The expression of hnRNPA2B1 is ubiquitously elevated in a variety of tumors and is associated with poor prognosis. Furthermore, hnRNPA2B1 is closely related to the immune cell infiltration and tumor microenvironment.

Inhibition of Angiogenesis by MiR-524-5p through Suppression of AKT and ERK Activation by Targeting CXCR7 in Colon Cancer Cells.

Increasing evidence shows that alterations in microRNA (miRNA) expression are involved in the occurrence and development of various malignant tumors, including colon cancer. MiRNA-524-5p has been reported to have anticancer activity in colon cancer. This study explored the influence of the miRNA-524-5p/CXCR7 axis on angiogenesis using colon cancer cells and further studied the mechanisms involved. We found that changing the expression of miRNA-524-5p can affect colonic proliferation, migration, and angiogenesis. Furthermore, angiogenesis induced by miRNA-524-5p overexpression was reversed by overexpression of CXCR7 in HT-29 cells, while the opposite was observed in Caco-2 cells. Furthermore, miRNA-524-5p inhibited the activation of AKT and ERK signaling by targeting CXCR7. Overall, our results indicated that the miRNA-524-5p/CXCR7 axis regulated angiogenesis in colon cancer cells through the AKT and ERK pathways.

Multi-perspective comparison of the immune microenvironment of primary colorectal cancer and liver metastases.

BACKGROUND: Liver metastases are a major contributor to the poor immunotherapy response in colorectal cancer patients. However, the distinctions in the immune microenvironment between primary tumors and liver metastases are poorly characterized. The goal of this study was to compare the expression profile of multiple immune cells to further analyze the similarities and differences between the microenvironments of liver metastases and the primary tumor. METHODS: Tissues from 17 patients with colorectal cancer who underwent resection of primary and liver metastases was analyzed using multispectral immunofluorescence. The expression of multiple immune cells (CD8, Foxp3, CD68, CD163, CD20, CD11c, CD66b, CD56, PD-L1, INF-γ, Ki67 and VEGFR-2) in the tumor center (TC), tumor invasive front (< 150 µm from the tumor center, TF) and peritumoral region (≥ 150 µm from the tumor center, PT) was evaluated via comparison. The expression of CD68 and CD163 in different regions was further analyzed based on the cell colocalization method. In addition, different immune phenotypes were studied and compared according to the degree of CD8 infiltration. RESULTS: The expression trends of 12 markers in the TF and TC regions were basically the same in the primary tumor and liver metastasis lesions. However, in comparison of the TF and PT regions, the expression trends were not identical between primary and liver metastases, especially CD163, which was more highly expressed in the PT region relative to the TF region. In the contrast of different space distribution, the expression of CD163 was higher in liver metastases than in the primary foci. Further analysis of CD68 and CD163 via colocalization revealed that the distribution of macrophages in liver metastases was significantly different from that in the primary foci, with CD68-CD163+ macrophages predominating in liver metastases. In addition, among the three immunophenotypes, CD163 expression was highest in the immune rejection phenotype. CONCLUSIONS: The immune cells found in the primary tumors of colorectal cancer differed from those in liver metastases in terms of their spatial distribution. More immunosuppressive cells were present in the liver metastases, with the most pronounced differential distribution found for macrophages. CD68-CD163+ macrophages may be associated with intrahepatic immunosuppression and weak immunotherapeutic effects.