Exosomes in the hypoxic TME: from release, uptake and biofunctions to clinical applications.

Hypoxia is a remarkable trait of the tumor microenvironment (TME). When facing selective pressure, tumor cells show various adaptive characteristics, such as changes in the expression of cancer hallmarks (increased proliferation, suppressed apoptosis, immune evasion, and so on) and more frequent cell communication. Because of the adaptation of cancer cells to hypoxia, exploring the association between cell communication mediators and hypoxia has become increasingly important. Exosomes are important information carriers in cell-to-cell communication. Abundant evidence has proven that hypoxia effects in the TME are mediated by exosomes, with the occasional formation of feedback loops. In this review, we equally focus on the biogenesis and heterogeneity of cancer-derived exosomes and their functions under hypoxia and describe the known and potential mechanism ascribed to exosomes and hypoxia. Notably, we call attention to the size change of hypoxic cancer cell-derived exosomes, a characteristic long neglected, and propose some possible effects of this size change. Finally, jointly considering recent developments in the understanding of exosomes and tumors, we describe noteworthy problems in this field that urgently need to be solved for better research and clinical application.

Comprehensive assessment of enhancing dewaterability of dredged sediments by starch-based flocculant.

Dredged sediment poses significant challenges for transportation and subsequent treatment due to its high water content and large volume. Coagulation, a common method of dewatering, can significantly enhance the dewatering performance of dredged sediment. This study synthesized a cationic starch-based flocculant [starch-3-chloro-2-hydroxypropyl trimethylammonium chloride (St-CTA)] through etherification for the flocculation dewatering of dredged sediment. The effectiveness and mechanism of St-CTA as a dewatering flocculant for dredged sediment were investigated. The results demonstrated that when the dosage of St-CTA was 12 mg g-1 TSS (total suspended solids), the dehydration property of dredged sediment substantially improved, with the specific resistance to filtration (SRF) decreasing by 93.3%, the capillary suction time (CST) by 93.5%, and the water content of the filter cake (WC) by 9.7%. The removal rate of turbidity of the supernatant from the conditioned dredged sediment reached 99.6%, accelerating the settling speed and effectively capturing and separating fine particles from the sediment. St-CTA significantly increased the median particle size (D50), altered the microstructure and extracellular polymeric substances (EPS) of the flocs, and increased the fractal dimension of the flocs, making them more compact and conducive to the formation of drainage channels. These findings confirm the feasibility of using potentially environmentally friendly St-CTA as a rapid dewatering conditioning agent for sediment.

Colony Stimulating Factor-1 and its Receptor in Gastrointestinal Malignant Tumors.

Gastrointestinal malignant tumor is the fourth most common cancer in the world and the second cause of cancer death. Due to the susceptibility to lymphatic metastasis and liver metastasis, the prognosis of advanced tumor patients is still poor till now. With the development of tumor molecular biology, the tumor microenvironment and the cytokines, which are closely related to the proliferation, infiltration and metastasis, have become a research hotspot in life sciences. Colony stimulating factor-1 (CSF-1), a polypeptide chain cytokine, and its receptor CSF-1R are reported to play important roles in regulating tumor-associated macrophages in tumor microenvironment and participating in the occurrence and development in diversities of cancers. Targeted inhibition of the CSF-1/CSF-1R signal axis has broad application prospects in cancer immunotherapy. Here, we reviewed the biological characters of CSF-1/CSF-1R and their relationship with gastrointestinal malignancies.

Non-coding RNA derived from extracellular vesicles in cancer immune escape: Biological functions and potential clinical applications.

The tumor microenvironment represents a dynamically composed matrix into which cancer cells and many other cell types are embedded to form organ-like structures. The tumor immune microenvironment (TIME), composed of immune cells, is an inseparable part of the tumor microenvironment. Extracellular vesicles (EVs) participate in the occurrence and development of tumors by delivering various biologically active molecules between cells; their role in cancer immune escape in particular has been widely proven. EVs can carry a wide array of cargo, such as non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs, which are selectively loaded by EVs, secreted, and transported to participate in the proliferation of immune cells. Hence, strategies to specifically target EV-ncRNAs could be attractive therapeutic options. In this review, we summarize the current research on the role of EV-ncRNAs in cancer immune escape, and discuss the latest research on the function and regulation mechanism of EV-ncRNAs in cancer immune escape, highlighting and elucidating the potential clinical applications of EV-ncRNAs, including in diagnosis and immunotherapy.

Rab GTPases: Central Coordinators of Membrane Trafficking in Cancer.

Tumor progression involves invasion, migration, metabolism, autophagy, exosome secretion, and drug resistance. Cargos transported by membrane vesicle trafficking underlie all of these processes. Rab GTPases, which, through coordinated and dynamic intracellular membrane trafficking alongside cytoskeletal pathways, determine the maintenance of homeostasis and a series of cellular functions. The mechanism of vesicle movement regulated by Rab GTPases plays essential roles in cancers. Therefore, targeting Rab GTPases to adjust membrane trafficking has the potential to become a novel way to adjust cancer treatment. In this review, we describe the characteristics of Rab GTPases; in particular, we discuss the role of their activation in the regulation of membrane transport and provide examples of Rab GTPases regulating membrane transport in tumor progression. Finally, we discuss the clinical implications and the potential as a cancer therapeutic target of Rab GTPases.

LINC00511 drives invasive behavior in hepatocellular carcinoma by regulating exosome secretion and invadopodia formation.

BACKGROUND: Tumor cells are known to release large numbers of exosomes containing active substances that participate in cancer progression. Abnormally expressed long noncoding RNAs (lncRNAs) have been confirmed to regulate multiple processes associated with tumor progression. However, the mechanism by which lncRNAs affect exosome secretion remains unclear. METHODS: The underlying mechanisms of long noncoding RNA LINC00511 (LINC00511) regulation of multivesicular body (MVB) trafficking, exosome secretion, invadopodia formation, and tumor invasion were determined through gene set enrichment analysis (GSEA), immunoblotting, nanoparticle tracking analysis, confocal colocalization analysis, electron microscopy, and invasion experiments. RESULTS: We revealed that the tumorigenesis process is associated with a significant increase in vesicle secretion in hepatocellular carcinoma (HCC). Additionally, LINC00511 was significantly more highly expressed in HCC tissues and is related to vesicle trafficking and MVB distribution. We also found that in addition to the formation of invadopodia in HCC progression, abnormal LINC00511 induces invadopodia formation in HCC cells by regulating the colocalization of vesicle associated membrane protein 7 (VAMP7) and synaptosome associated protein 23 (SNAP23) to induce the invadopodia formation, which are key secretion sites for MVBs and control exosome secretion. Finally, we revealed that LINC0051-induced invadopodia and exosome secretion were involved in tumor progression. CONCLUSIONS: Our experiments revealed novel findings on the relationship between LINC00511 dysregulation in HCC and invadopodia production and exosome secretion. This is a novel mechanism by which LINC00511 regulates invadopodia biogenesis and exosome secretion to further promote cancer progression.

CISD2 Promotes Resistance to Sorafenib-Induced Ferroptosis by Regulating Autophagy in Hepatocellular Carcinoma.

PURPOSE: Sorafenib is a multi-kinase inhibitor that is used as a standard treatment for advanced hepatocellular carcinoma (HCC). However, the mechanism of sorafenib resistance in HCC is still unclear. It has been shown that CISD2 expression is related to the progression and poor prognosis of HCC. Here, we show a new role for CISD2 in sorafenib resistance in HCC. METHODS: Bioinformatic analysis was used to detect the expression of negative regulatory genes of ferroptosis in sorafenib-resistant samples. The concentration gradient method was used to establish sorafenib-resistant HCC cells. Western blot was used to detect the protein expression of CISD2, LC3, ERK, PI3K, AKT, mTOR, and Beclin1 in HCC samples. Quantitative real-time PCR (qPCR) was used to detect gene expression. CISD2 shRNA and Beclin1 shRNA were transfected to knock down the expression of the corresponding genes. Cell viability was detected by a CCK-8 assay. ROS were detected by DCFH-DA staining, and MDA and GSH were detected with a Lipid Peroxidation MDA Assay Kit and Micro Reduced Glutathione (GSH) Assay Kit, respectively. Flow cytometry was used to detect apoptosis and the levels of ROS and iron ions. RESULTS: CISD2 was highly expressed in HCC cells compared with normal cells and was associated with poor prognosis in patients. Knockdown of CISD2 promoted a decrease in the viability of drug-resistant HCC cells. CISD2 knockdown promoted sorafenib-induced ferroptosis in resistant HCC cells. The levels of ROS, MDA, and iron ions increased, but the change in GSH was not obvious. Knockdown of CISD2 promoted uncontrolled autophagy in resistant HCC cells. Inhibition of autophagy attenuated CISD2 knockdown-induced ferroptosis. The autophagy promoted by CISD2 knockdown was related to Beclin1. When CISD2 and Beclin1 were inhibited, the effect on ferroptosis was correspondingly weakened. CONCLUSION: Inhibition of CISD2 promoted sorafenib-induced ferroptosis in resistant cells, and this process promoted excessive iron ion accumulation through autophagy, leading to ferroptosis. The combination of CISD2 inhibition and sorafenib treatment is an effective therapeutic strategy for resistant HCC.

IKKß activation promotes amphisome formation and extracellular vesicle secretion in tumor cells.

Intracellular organelle cross-talk is a new and important research area. Under stress conditions, the coordinated action of the autophagy and endosomal systems in tumor cells is essential for maintaining cellular homeostasis and survival. The activation of the IκB kinase (IKK) complex is also involved in the regulation of stress and homeostasis in tumor cells. Here, we try to explore the effects of constitutively active IKKß subunits (CA-IKKß) on autophagy and endosomal system interactions. We confirm that CA-IKKß induces accumulation of autophagosomes and their fusion with MVBs to form amphisomes in cancer cells, and also drives the release of EVs containing autophagy components through an amphisome-dependent mechanism. We further demonstrate that CA-IKKß inhibits the expression of RAB7, thereby weakening the lysosomal-dependent degradation pathway. CA-IKKß also induces phosphorylation of SNAP23 at Ser95 instead of Ser110, which further promotes amphisome-plasma membrane fusion and sEV secretion. These results indicate that CA-IKKß drives the formation and transport of amphisomes, thereby regulating tumor cell homeostasis, which may illuminate a special survival mechanism in tumor cells under stress.

WNT/ß-catenin signaling in the development of liver cancers.

The WNT/ß-catenin signaling pathway is a highly conserved and tightly controlled molecular mechanism that regulates embryonic development, cellular proliferation and differentiation. Of note, accumulating evidence has shown that the aberrant of WNT/ß-catenin signaling promotes the development and/or progression of liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the two most prevalent primary liver tumours in adults. There are two different WNT signaling pathways have been identified, which were termed non-canonical and canonical pathways, the latter involving the activation of ß-catenin. ß-catenin, acting as an intracellular signal transducer in the WNT signaling pathway, is encoded by CTNNB1 and plays a critical role in tumorigenesis. In the past research, most liver tumors have mutations in genes encoding key components of the WNT/ß-catenin signaling pathway. In addition, several of other signaling pathways also can crosswalk with ß-catenin. In this review, we discuss the most relevant molecular mechanisms of action and regulation of WNT/ß-catenin signaling in the development and pathophysiology of liver cancers, as well as in the development of therapeutics.

Emerging mechanisms and applications of ferroptosis in the treatment of resistant cancers.

The development of chemotherapy drugs has promoted anticancer treatment, but the effect on tumours is not clear because of treatment resistance; thus, it is necessary to further understand the mechanism of cell death to explore new therapeutic targets. As a new type of programmed cell death, ferroptosis is increasingly being targeted in the treatment of many cancers with clinical drugs and experimental compounds. Ferroptosis is stimulated in tumours with inherently high levels of ferrous ions by a reaction with abundant polyunsaturated fatty acids and the inhibition of antioxidant enzymes, which can overcome treatment resistance in cancers mainly through GPX4. In this review, we focus on the intrinsic cellular regulators against ferroptosis in cancer resistance, such as GPX4, NRF2 and the thioredoxin system. We summarize the application of novel compounds and drugs to circumvent treatment resistance. We also introduce the application of nanoparticles for the treatment of resistant cancers. In conclusion, targeting ferroptosis represents a considerable strategy for resistant cancer treatment.

Scutellarin inhibits the metastasis and cisplatin resistance in glioma cells.

BACKGROUND: Scutellarin is a natural flavone compound that possesses anti-tumor and chemosensitization effects in several cancers. However, the effects of scutellarin on metastasis and chemoresistance in glioma have not been illustrated. METHODS: Glioma cells were treated with scutellarin in the presence or absence of LY294002. Cell proliferation was measured using a Cell Proliferation BrdU ELISA kit. Cell migration and invasion were analyzed using transwell assay. The expressions of E-cadherin, N-cadherin, vimentin, p-PI3K, PI3K, p-AKT, AKT, p-mTOR and mTOR were measured using Western blot. Furthermore, cells were incubated in the presence of cisplatin with or without the pretreatment of scutellarin. Cell viability was detected by the MTT assay. Cell apoptosis was measured using a histone/DNA ELISA detection kit. The expressions of ABCB1 and ABCG2 were detected using Western blot. RESULTS: In the present study, we found that scutellarin inhibited the proliferation, migration, and invasion of glioma cells. Scutellarin induced E-cadherin expression and reduced the expressions of N-cadherin, and vimentin in glioma cells. Our results also revealed that scutellarin enhanced chemosensitivity to cisplatin, as evidenced by the decreased cell viability to cisplatin and induced cell apoptosis. Moreover, scutellarin inhibited the expressions of ATP-binding cassette subfamily B member 1 and ATP-binding cassette sub-family G member 2 in cisplatin-resistant glioma cells. Scutellarin also prevented the activation of phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway. CONCLUSION: The data suggested that scutellarin suppressed metastasis and chemoresistance in glioma cells. Scutellarin might be a new therapeutic approach for the glioma therapy.

Knockdown of TRIM37 suppresses the proliferation, migration and invasion of glioma cells through the inactivation of PI3K/Akt signaling pathway.

Tripartite motif 37 (TRIM37), a member of the TRIM protein family, was involved in the tumorigenesis of several types of cancer. However, the expression pattern and role of TRIM37 in glioma remain unclear. Therefore, the aim of the present study was to investigate the role of TRIM37 in glioma, and to determine the molecular mechanisms. Our results demonstrated that TRIM37 was highly expressed in human glioma tissues and cell liens. Additionally, knockdown of TRIM37 dramatically inhibited the proliferation, migration/invasion, and the epithelial-mesenchymal transition (EMT) phenotype in glioma cells. Furthermore, knockdown of TRIM37 significantly reduced the levels of phosphorylated PI3K and Akt in U87MG cells, and an activator of PI3K/Akt signaling (SC79) partly reversed the inhibitory effects of si-TRIM37 on glioma cell proliferation and migration. Taken together, our results demonstrated that TRIM37 functions as an oncogene in the development and progression of glioma. TRIM37 knockdown inhibited the proliferation and invasion of human glioma cells at least in part through the inactivation of PI3K/Akt signaling pathway.

Retracted Article: TRIM22 functions as an oncogene in gliomas through regulating the Wnt/ß-catenin signaling pathway.

The tripartite motif-containing (TRIM) family is a group of proteins that are implicated in a plethora of pathological conditions. TRIM22 has been found to be involved in various cancers; however, the role of TRIM22 in gliomas has not been reported. The present study aimed to evaluate the expression pattern of TRIM22 and its function in gliomas. TRIM22 expressions in glioma tissues and cell lines were measured by RT-PCR and western blot analysis. To knockdown TRIM22 by small hairpin RNAs (shTRIM22), the U118 cells were transfected with pLKO.1-shTRIM22 plasmid or pLKO.1 plasmid. Cell proliferation was measured using CCK-8 assay. Transwell assays were performed to evaluate the migration and invasion. The epithelial-mesenchymal transition (EMT) was assessed by detecting the expressions of E-cadherin, N-cadherin and vimentin with western blot analysis. A xenograft mouse model was established to evaluate the effect of TRIM22 silencing on tumor growth in vivo. The expressions of ß-catenin, cyclin D1, and c-Myc were analyzed by western blot analysis. TRIM22 was significantly overexpressed in glioma tissues and cell lines. In vitro studies demonstrated that TRIM22 knockdown inhibited cell proliferation, migration, and invasion. Additionally, TRIM22 silencing increased the expressions of E-cadherin, and decreased the expressions of N-cadherin and vimentin. Nude mouse xenograft assay showed that TRIM22 silencing inhibited tumor growth in vivo. Furthermore, silencing of TRIM22 inhibited the activation of the Wnt/ß-catenin pathway. Treatment with LiCl, an activator of the Wnt/ß-catenin pathway, attenuated the effects of shTRIM22 on U118 cells. Silencing of TRIM22 inhibited proliferation, migration and invasion, as well as repressing the EMT process in glioma cells. The Wnt/ß-catenin pathway was involved in the effect of TRIM22.

PAQR3 inhibits the proliferation, migration and invasion in human glioma cells.

Progestin and AdipoQ Receptor 3 (PAQR3), a member of the PAQR family, is down-regulated in several types of cancers and has been closely associated with tumor progression and development. However, little is known about the functions of PAQR3 in the tumorigenesis of human glioma. Therefore, in this report, we investigated the role of PAQR3 in human glioma. Our results showed that the expression of PAQR3 was significantly reduced in human glioma tissues and cell lines. PAQR3 overexpression inhibited the proliferation of glioma cells in vitro and attenuated tumor xenograft growth in vivo. In addition, PAQR3 overexpression suppressed the migration and invasion of glioma cells, as well as prevented the EMT process. Mechanistic studies demonstrated that PAQR3 overexpression significantly down-regulated the levels of phosphorylated PI3K and Akt in U251 cells. In conclusion, these results demonstrated that PAQR3 inhibited the proliferation, migration and invasion in glioma cells, at least in part, through the inactivation of PI3K/Akt signaling pathway. Therefore, PAQR3 may be a therapeutic target for the treatment of glioma.

MicroRNA-150 regulates glycolysis by targeting von Hippel-Lindau in glioma cells.

Warburg effect, characterized by enhanced glycolysis and lactate production, even under aerobic conditions, is one of the hallmarks of cancer cells. However, the mechanism underlying this phenomenon remains poorly understood. Previous studies have shown that microRNA-150 (miR-150) is significantly up-regulated in various malignancies and represents a putative onco-miRNA in human cancers. In the present study, we aim to investigate the functional significance and molecular target of miR-150 in glioma. As a result, von Hippel-Lindau (VHL), which is a specific E3 ligase for hypoxia inducible factor 1 (HIF1α), was identified as a novel target of miR-150. Consistently, cells overexpressing miR-150 exhibited a metabolic shift, including enhanced glucose uptake and lactate production, which led to a rapid growth of glioma cells. Therefore, our results suggest that miR-150 modulates the Warburg effect in glioma via VHL/HIF1α and might provide a novel option for future treatments for glioma.

MicroRNA-214 targets PCBP2 to suppress the proliferation and growth of glioma cells.

PCBP2, a member of the poly(C)-binding protein (PCBP) family, is involved in posttranscriptional and translational regulation by interacting with single-stranded poly(C) motifs in target mRNAs. Recent studies have shown that PCBP2 is overexpressed and plays an important role in human cancers, including glioma. However, the molecular basis for its up-regulation remains poorly understood. Here, we show that microRNA-214 (miR-214) interacts with the 3'-untranslated region of PCBP2 mRNA and induces its degradation, leading to reductions in its protein expression. As a result, overexpression of miR-214 mimics significantly inhibited, while its antisense oligos proliferation and growth of glioma cells. Restoration of PCBP2 remarkably reversed the tumor-suppressive effects of miR-214 on cell proliferation and growth. In summary, our data indicate that miR-214 may function as tumor suppressor in glioma by targeting PCBP2.

Wnt/ß-catenin up-regulates Midkine expression in glioma cells.

Midkine, also known as neurite growth-promoting factor 2 (NEGF2), plays an important role in cell proliferation, apoptosis and differentiation. Recent studies have shown that Midkine is up-regulated in several types of human cancers. However, the molecular mechanism for its up-regulation remains poorly understood. Activation of Wnt/ß-catenin signaling is viewed as crucial for multiple tumor growth and metastasis, including glioma. In the present study, we found that Wnt3a administration or transfection of a constitutively activated ß-catenin promoted Midkine expression in glioma cells. We further identified a TCF/LEF binding site, with which beta-catenin interacts, on the proximal promoter region of Midkine gene, by luciferase reporter and chromatin immunoprecipitation assays. Thus, our results suggest a previously unknown Wnt/ß-catenin/Midkine molecular network controlling glioma development.