The roles and molecular mechanisms of non-coding RNA in cancer metabolic reprogramming.

One of the key features of cancer is energy metabolic reprogramming which is tightly related to cancer proliferation, invasion, metastasis, and chemotherapy resistance. NcRNAs are a class of RNAs having no protein-coding potential and mainly include microRNAs, lncRNAs and circRNAs. Accumulated evidence has suggested that ncRNAs play an essential role in regulating cancer metabolic reprogramming, and the altered metabolic networks mediated by ncRNAs primarily drive carcinogenesis by regulating the expression of metabolic enzymes and transporter proteins. Importantly, accumulated research has revealed that dysregulated ncRNAs mediate metabolic reprogramming contributing to the generation of therapeutic tolerance. Elucidating the molecular mechanism of ncRNAs in cancer metabolic reprogramming can provide promising metabolism-related therapeutic targets for treatment as well as overcome therapeutic tolerance. In conclusion, this review updates the latest molecular mechanisms of ncRNAs related to cancer metabolic reprogramming.

Rac1 promotes the reprogramming of glucose metabolism and the growth of colon cancer cells through upregulating SOX9.

Metabolic reprogramming is the survival rule of tumor cells, and tumor cells can meet their high metabolic requirements by changing the energy metabolism mode. Metabolic reprogramming of tumor cells is an important biochemical basis of tumor malignant phenotypes. Ras-related C3 botulinum toxin substrate 1 (Rac1) is abnormally expressed in a variety of tumors and plays an important role in the proliferation, invasion, and migration of tumor cells. However, the role of Rac1 in tumor metabolic reprogramming is still unclear. Herein, we revealed that Rac1 was highly expressed in colon cancer tissues and cell lines. Rac1 promotes the proliferation, migration, and invasion of colon cancer cells by upregulating SOX9, which as a transcription factor can directly bind to the promoters of HK2 and G6PD genes and regulate their transcriptional activity. Rac1 upregulates the expression of SOX9 through the PI3K/AKT signaling pathway. Moreover, Rac1 can promote glycolysis and the activation of the pentose phosphate pathway in colon cancer cells by mediating the axis of SOX9/HK2/G6PD. These findings reveal novel regulatory axes involving Rac1/SOX9/HK2/G6PD in the development and progression of colon cancer, providing novel promising therapeutic targets.

LPLUNC1 reduces glycolysis in nasopharyngeal carcinoma cells through the PHB1-p53/c-Myc axis.

Cancer cells prefer glycolysis to support their proliferation. Our previous studies have shown that the long palate, lung, and nasal epithelial cell clone 1 (LPLUNC1) can upregulate prohibitin 1 (PHB1) expression to inhibit the proliferation of nasopharyngeal carcinoma (NPC) cells. Given that PHB1 is an important regulator of cell energy metabolism, we explored whether and how LPLUNC1 regulated glucose glycolysis in NPC cells. LPLUNC1 or PHB1 overexpression decreased glycolysis and increased oxidative phosphorylation (OXPHOS)-related protein expression in NPC cells, promoting phosphorylated PHB1 nuclear translocation through 14-3-3σ. LPLUNC1 overexpression also increased p53 but decreased c-Myc expression in NPC cells, which were crucial for the decrease in glycolysis and increase in OXPHOS-related protein expression induced by LPLUNC1 overexpression. Finally, we found that treatment with all-trans retinoic acid (ATRA) reduced the viability and clonogenicity of NPC cells, decreased glycolysis, and increased OXPHOS-related protein expression by enhancing LPLUNC1 expression in NPC cells. Therefore, the LPLUNC1-PHB1-p53/c-Myc axis decreased glycolysis in NPC cells, and ATRA upregulated LPLUNC1 expression, ATRA maybe a promising drug for the treatment of NPC.

Impacts and mechanisms of alternative mRNA splicing in cancer metabolism, immune response, and therapeutics.

Alternative pre-mRNA splicing (AS) provides the potential to produce diversity at RNA and protein levels. Disruptions in the regulation of pre-mRNA splicing can lead to diseases. With the development of transcriptome and genome sequencing technology, increasing diseases have been identified to be associated with abnormal splicing of mRNAs. In tumors, abnormal alternative splicing frequently plays critical roles in cancer pathogenesis and may be considered as new biomarkers and therapeutic targets for cancer intervention. Metabolic abnormalities and immune disorders are important hallmarks of cancer. AS produces multiple different isoforms and diversifies protein expression, which is utilized by the immune and metabolic reprogramming systems to expand gene functions. The abnormal splicing events contributed to tumor progression, partially due to effects on immune response and metabolic reprogramming. Herein, we reviewed the vital role of alternative splicing in regulating cancer metabolism and immune response. We discussed how alternative splicing regulates metabolic reprogramming of cancer cells and antitumor immune response, and the possible strategies to targeting alternative splicing pathways or splicing-regulated metabolic pathway in the context of anticancer immunotherapy. Further, we highlighted the challenges and discuss the perspectives for RNA-based strategies for the treatment of cancer with abnormally alternative splicing isoforms.

Regulation of cancer progression by circRNA and functional proteins.

Circular RNAs (circRNAs) are closed back-splicing products of precursor mRNA in eukaryotes. Compared with linear mRNAs, circRNAs have a special structure and stable expression. A large number of studies have provided different regulatory mechanisms of circRNAs in tumors. Challenges exist in understanding the control of circRNAs because of their sequence overlap with linear mRNA. Here, we survey the most recent progress regarding the regulation of circRNA biogenesis by RNA-binding proteins, one of the vital functional proteins. Furthermore, substantial circRNAs exert compelling biological roles by acting as protein sponges, by being translated themselves or regulating posttranslational modifications of proteins. This review will help further explore more types of functional proteins that interact with circRNA in cancer and reveal other unknown mechanisms of circRNA regulation.

Systematic analysis of inflammation and pain pathways in a mouse model of gout.

Gout is a prevalent and painful inflammatory arthritis, and its global burden continues to rise. Intense pain induced by gout attacks is a major complication of gout. However, systematic studies of gout inflammation and pain are lacking. Using a monosodium urate (MSU) crystal-induced gout model, we performed genome-wide transcriptome analysis of the inflamed ankle joint, dorsal root ganglion (DRG), and spinal cord of gouty mice. Our results revealed important transcriptional changes, including highly elevated inflammation and broad activation of immune pathways in both the joint and the nervous system, in gouty mice. Integrated analysis showed that there was a remarkable overlap between our RNAseq and human genome-wide association study (GWAS) of gout; for example, the risk gene, stanniocalcin-1 (STC1) showed significant upregulation in all three tissues. Interestingly, when compared to the transcriptomes of human osteoarthritis (OA) and rheumatoid arthritis (RA) joint tissues, we identified significant upregulation of cAMP/cyclic nucleotide-mediated signaling shared between gouty mice and human OA with high knee pain, which may provide excellent drug targets to relieve gout pain. Furthermore, we investigated the common and distinct transcriptomic features of gouty, inflammatory pain, and neuropathic pain mouse models in their DRG and spinal cord tissues. Moreover, we discovered distinct sets of genes with significant differential alternative splicing or differential transcript usage in each tissue, which were largely not detected by conventional differential gene expression analysis approaches. Based on these results, our study provided a more accurate and comprehensive depiction of transcriptomic alterations related to gout inflammation and pain.

The function of prohibitins in mitochondria and the clinical potentials.

Prohibitins (PHBs) are a class of highly evolutionarily conserved proteins that widely distribute in prokaryotes and eukaryotes. PHBs function in cell growth and proliferation or differentiation, regulating metabolism and signaling pathways. PHBs have different subcellular localization in eukaryotes, but they are mainly located in mitochondria. In the mitochondria, PHBs stabilize the structure of the mitochondrial membrane and regulate mitochondrial autophagy, mitochondrial dynamics, mitochondrial biogenesis and quality control, and mitochondrial unfolded protein response. PHBs has shown to be associated with many diseases, such as mitochondria diseases, cancers, infectious diseases, and so on. Some molecule targets of PHBs can interfere with the occurrence and development of diseases. Therefore, this review clarifies the functions of PHBs in mitochondria, and provides a summary of the potential values in clinics.

Long noncoding RNA EPB41L4A-AS1 functions as an oncogene by regulating the Rho/ROCK pathway in colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. In terms of cancer-related death, colon cancer ranks second and third among men and women, respectively, and the incidence is increasing annually. Accumulating evidence have indicated that long noncoding RNA (lncRNA) plays an important role in tumorigenesis. In this study, we found that lncRNA EPB41L4A-AS1 was highly expressed in CRC tissues and was associated with poor prognosis and tumor metastasis in patients with CRC. In vitro studies showed that the knockdown of EPB41L4A-AS1 inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition of CRC cells. Mechanically, we found that EPB41L4A-AS1 may participate in the development of CRC by activating the Rho/Rho-associated protein kinase signaling pathway. Collectively, these results demonstrated that EPB41L4A-AS1 can promote the proliferation, invasion, and migration of CRC, and it may be a novel biomarker for the diagnosis and targeted treatment of CRC.

Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments.

BACKGROUND: Vasculogenic mimicry (VM) is a recently discovered angiogenetic process found in many malignant tumors, and is different from the traditional angiogenetic process involving vascular endothelium. It involves the formation of microvascular channels composed of tumor cells; therefore, VM is considered a new model for the formation of new blood vessels in aggressive tumors, and can provide blood supply for tumor growth. Many studies have pointed out that in recent years, some clinical treatments against angiogenesis have not been satisfactory possibly due to the activation of VM. Although the mechanisms underlying VM have not been fully elucidated, increasing research on the soil "microenvironment" for tumor growth suggests that the initial hypoxic environment in solid tumors is inseparable from VM. MAIN BODY: In this review, we describe that the stemness and differentiation potential of cancer stem cells are enhanced under hypoxic microenvironments, through hypoxia-induced epithelial-endothelial transition (EET) and extracellular matrix (ECM) remodeling to form the specific mechanism of vasculogenic mimicry; we also summarized some of the current drugs targeting VM through these processes, suggesting a new reference for the clinical treatment of tumor angiogenesis. CONCLUSION: Overall, the use of VM inhibitors in combination with conventional anti-angiogenesis treatments is a promising strategy for improving the effectiveness of targeted angiogenesis treatments; further, considering the importance of hypoxia in tumor invasion and metastasis, drugs targeting the hypoxia signaling pathway seem to achieve good results.

The cancer metabolic reprogramming and immune response.

The overlapping metabolic reprogramming of cancer and immune cells is a putative determinant of the antitumor immune response in cancer. Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune response through both the release of metabolites and affecting the expression of immune molecules, such as lactate, PGE2, arginine, etc. Actually, this energetic interplay between tumor and immune cells leads to metabolic competition in the tumor ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function. More interestingly, metabolic reprogramming is also indispensable in the process of maintaining self and body homeostasis by various types of immune cells. At present, more and more studies pointed out that immune cell would undergo metabolic reprogramming during the process of proliferation, differentiation, and execution of effector functions, which is essential to the immune response. Herein, we discuss how metabolic reprogramming of cancer cells and immune cells regulate antitumor immune response and the possible approaches to targeting metabolic pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments between immunotherapy and metabolic intervening that could be used to better unleash the potential of anticancer therapies.

Lipid Metabolism and Immune Checkpoints.

Immune checkpoints are essential for the regulation of immune cell functions. Although the abrogation of immunosurveillance of tumor cells is known, the regulators of immune checkpoints are not clear. Lipid metabolism is one of the important metabolic activities in organisms. In lipid metabolism, a large number of metabolites produced can regulate the gene expression and activation of immune checkpoints through various pathways. In addition, increasing evidence has shown that lipid metabolism leads to transient generation or accumulation of toxic lipids that result in endoplasmic reticulum (ER) stress and then regulate the transcriptional and posttranscriptional modifications of immune checkpoints, including transcription, protein folding, phosphorylation, palmitoylation, etc. More importantly, the lipid metabolism can also affect exosome transportation of checkpoints and the degradation of checkpoints by affecting ubiquitination and lysosomal trafficking. In this chapter, we mainly empathize on the roles of lipid metabolism in the regulation of immune checkpoints, such as gene expression, activation, and degradation.

[Bibenzyls from Dendrobium officinale].

Fifteen bibenzyls were isolated and purified from the ethyl acetate extract of the stems of Dendrobium officinale by macroporous resin, MCI, silica gel, Sephadex LH-20, and ODS column chromatographies, as well as preparative thin-layer chromatography and preparative HPLC. The structures of compounds were identified according to the spectra data of ~1H-NMR, ~(13)C-NMR, and MS, and the physical and physiochemical properties: dendrocandin X(1), 3,4'-dihydroxy-4,5-dimethoxybibenzyl(2), 6″-de-O-methyldendrofindlaphenol A(3), 3,4-dihydroxy-4',5-dimethoxybibenzyl(4), dendrosinen B(5), 3,4,4'-trihydroxy-5-methoxybibenzyl(6), 3,3'-dihydroxy-4,5-dimethoxybibenzyl(7), 3,4'-dihydroxy-5-methoxybibenzyl(8), moscatilin(9), gigantol(10), 4,4'-dihydroxy-3,5-dimethoxybibenzyl(11), 3,4',5-trihydroxy-3'-methoxybibenzyl(12), 3-O-methylgigantol(13), dendrocandin U(14), and dendrocandin N(15). Compound 1 was a novel compound. Compound 2 was isolated from Dendrobium species for the first time. Compounds 3-7 were isolated from D. officinale for the first time.

Separation of 2-Chloropyridine/3-Chloropyridine by Nonporous Adaptive Crystals of Pillararenes with Different Substituents and Cavity Sizes.

Two monochloropyridine isomers, 2-chloropyridine (2-CP) and 3-chloropyridine (3-CP), are in need of a more effective separation method besides rectification. Herein we offer a facile and energy-saving adsorptive separation strategy using nonporous adaptive crystals of perethylated pillar[5]arene (EtP5), perethylated pillar[6]arene (EtP6), perbromoethylated pillar[5]arene (BrP5), and perbromoethylated pillar[6]arene (BrP6), which possess different cavity sizes and substituents and have never been employed in the separation of single-substituted heterocyclic aromatic compounds. BrP6 crystals show a marked preference for 2-CP in the equimolar mixture of 2-CP and 3-CP, affording it with 96.4% purity. Single crystal diffraction experiments demonstrate that BrP6 has stronger host-guest interactions with 2-CP than 3-CP. The cycling experiments demonstrate that BrP6 crystals can be used at least five times without losing their adsorption selectivity or capacity.

Highly Selective Removal of Trace Isomers by Nonporous Adaptive Pillararene Crystals for Chlorobutane Purification.

Removal of trace chlorobutane (CB) isomers is highly desired to produce high grade 1-chlorobutane (1-CB) and 2-chlorobutane (2-CB). Here, we report that nonporous adaptive crystals (NACs) of perethylated pillar[5]arene (EtP5) and pillar[6]arene (EtP6) effectively remove trace CB isomers. EtP5 NACs can remove trace 1-CB (2%) from 2-CB to improve its purity from 98.0% to 99.9%, while EtP6 NACs can remove trace 2-CB from 1-CB to improve its purity from 98.0% to 99.9%. The adsorption of trace CB isomers results in the formation of new CB-loaded crystal structures, whose thermostability is higher than their corresponding isomer-loaded structures. This determines the selectivity of NACs toward the trace CB isomers. Reversible transformations between nonporous guest-free and guest-loaded structures make EtP5 and EtP6 highly recyclable.

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy.

Immune checkpoint blockade targeting PD-1/PD-L1 has promising therapeutic efficacy in a variety of tumors, but resistance during treatment is a major issue. In this review, we describe the utility of PD-L1 expression levels, mutation burden, immune cell infiltration, and immune cell function for predicting the efficacy of PD-1/PD-L1 blockade therapy. Furthermore, we explore the mechanisms underlying immunotherapy resistance caused by PD-L1 expression on tumor cells, T cell dysfunction, and T cell exhaustion. Based on these mechanisms, we propose combination therapeutic strategies. We emphasize the importance of patient-specific treatment plans to reduce the economic burden and prolong the life of patients. The predictive indicators, resistance mechanisms, and combination therapies described in this review provide a basis for improved precision medicine.

Correction to: Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy.

After publication of the article [1], authors found out that Fig. 1 was inadvertently replaced.

Metabolomics Analysis of the Effect of Hydrogen-Rich Water on Myocardial Ischemia-Reperfusion Injury in Rats.

To investigate the effect of hydrogen-rich water on myocardial tissue metabolism in a myocardial ischemia-reperfusion injury (MIRI) rat model. Twelve rats were randomly divided into a hydrogen-rich water group and a control group of size 6 each. After the heart was removed, it was fixed in the Langendorff device, and the heart was perfused with 37 °C perfusion solution pre-balanced with oxygen. The control group was perfused with Kreb's-Ringers (K-R) solution, and the hydrogen-rich water group was perfused with K-R solution + hydrogen-rich water. Liquid Chromatograph Mass Spectrometer (LC-MS) analysis platform was used for metabolomics research. Principle component analysis (PCA), partial least squares discriminant analysis (PLS-DA), orthogonal partial least squares discriminant analysis (OPLS-DA), Variable importance in projection (VIP) value of OPLS-DA model (threshold value ≥1) were employed with independent sample T Test (p < 0.05) to find differentially expressed metabolites, and screen for differential metabolic pathways. VIP (OPLS-DA) analysis was performed with T test, and the metabolites of the control group and the hydrogen-rich water group were significantly different, and the glycerophospholipid metabolism was screened. Seven myocardial ischemia-reperfusion injury (MIRI)-related signaling pathways were identified, including glycerophospholipid metabolism, glycosylphosphatidylinositol (GPI) anchored biosynthesis, and purine metabolism, as well as 10 biomarkers such as phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine. Hydrogen-rich water regulates the metabolic imbalance that could change MIRI myocardial tissue metabolism, and alleviate ischemia-reperfusion injury in isolated hearts of rats through multiple signaling pathways.

Separation of Monochlorotoluene Isomers by Nonporous Adaptive Crystals of Perethylated Pillar[5]arene and Pillar[6]arene.

Separation of monochlorotoluene isomers is a vital process to obtain highly pure p-chlorotoluene, which is irreplaceable in the production of medicines and pesticides. However, traditional separation methods suffer from great energy consumption, cumbersome operation or use of organic desorbents. Herein, an energy-efficient and environmentally friendly method is developed through an absorptive separation strategy based on nonporous adaptive crystals of perethylated pillar[5]arene (EtP5) and pillar[6]arene (EtP6). EtP5 and EtP6 crystals separate p-chlorotoluene from a p-chlorotoluene/o-chlorotoluene equimolar mixture with purities of 99.1% and 96.1%, respectively and show no decrease in selectivity upon cycling. The selectivity is attributed to both the stability of the final crystal structure upon guest capture and suitable host cavity size/shape. Besides, we discovered the gate-opening behavior changes of EtP5 crystals at different temperatures after absorption of p-chlorotoluene/o-chlorotoluene mixtures with various p-chlorotoluene fractions, which is helpful to understand the thermodynamics of the absorption process.

Cis-Trans Selectivity of Haloalkene Isomers in Nonporous Adaptive Pillararene Crystals.

The separation of haloalkene cis-trans isomers is difficult to achieve, yet highly desired in the chemical industry. Here, we report an energy-efficient adsorptive separation of 1,4-dichloro-2-butene (DCB) cis-trans isomers using nonporous adaptive crystals of perethylated pillararenes. Adaptive perethylated pillar[6]arene (EtP6) crystals separate the trans-DCB isomer from its cis isomer with high selectivity while perethylated pillar[5]arene (EtP5) crystals adsorb cis-trans DCB isomers without selectivity. The selectivity of EtP6 derives from the difference in the thermodynamic stabilities of guest-loaded EtP6 crystal structures upon capture of cis-trans DCB isomers, while the structural similarity of guest-loaded EtP5 leads to the loss of selectivity. EtP6 is highly recyclable due to the reversible transformations between guest-free and guest-loaded structures.

Effect of hydrogen-rich water on the Nrf2/ARE signaling pathway in rats with myocardial ischemia-reperfusion injury.

The effects of hydrogen-rich water on oxidative stress via the Nrf2/ARE signaling pathway were studied in rats with myocardial ischemia-reperfusion injury (MIRI). Sixty rats were randomly divided into a hydrogen-rich water group and a control group, with 30 rats in each group. The two groups were randomly divided into three groups: pre-ischemic period, ischemic period and reperfusion period. After the heart was removed, it was fixed in a Langendorff device and perfused with an oxygen-balanced 37 °C perfusate. The control group was perfused with Kreb's-Ringers (K-R) solution, and the hydrogen-rich water group was perfused with K-R solution + hydrogen-rich water. The levels of mRNA and protein of Nrf2, NQO1, HO-1 and SOD-1 in cardiomyocytes were detected by RT-qPCR, immunohistochemistry (IHC) and Western blot analysis. SOD activity and MDA content were determined. Hydrogen-rich water increased the activation of the Nrf2/ARE signaling pathway, and the levels of mRNA and protein Nrf2, NQO1, HO-1 and SOD-1 were significantly increased (P < 0.05) in the ischemia-reperfusion period compared with the ischemic period. In the control group, the levels of mRNA and protein of Nrf2, NQO1, HO-1 and SOD-1 were significantly decreased (P < 0.05) in the ischemia-reperfusion period compared with the ischemic period. Compared with the ischemic period, the ischemia-reperfusion phase showed significantly increased SOD activity and significantly decreased MDA content in the hydrogen-rich water group, while SOD activity was significantly decreased, and MDA content was significantly increased in the control group (P < 0.05). Hydrogen-rich water can activate the Nrf2/ARE signaling pathway, alleviate ischemia-reperfusion injury in isolated rat hearts and reduce the oxidative stress level of myocardial tissue.