KCNK1 promotes proliferation and metastasis of breast cancer cells by activating lactate dehydrogenase A (LDHA) and up-regulating H3K18 lactylation.

Breast cancer is the most prevalent malignancy and the most significant contributor to mortality in female oncology patients. Potassium Two Pore Domain Channel Subfamily K Member 1 (KCNK1) is differentially expressed in a variety of tumors, but the mechanism of its function in breast cancer is unknown. In this study, we found for the first time that KCNK1 was significantly up-regulated in human breast cancer and was correlated with poor prognosis in breast cancer patients. KCNK1 promoted breast cancer proliferation, invasion, and metastasis in vitro and vivo. Further studies unexpectedly revealed that KCNK1 increased the glycolysis and lactate production in breast cancer cells by binding to and activating lactate dehydrogenase A (LDHA), which promoted histones lysine lactylation to induce the expression of a series of downstream genes and LDHA itself. Notably, increased expression of LDHA served as a vicious positive feedback to reduce tumor cell stiffness and adhesion, which eventually resulted in the proliferation, invasion, and metastasis of breast cancer. In conclusion, our results suggest that KCNK1 may serve as a potential breast cancer biomarker, and deeper insight into the cancer-promoting mechanism of KCNK1 may uncover a novel therapeutic target for breast cancer treatment.

Immunotherapy and the ovarian cancer microenvironment: Exploring potential strategies for enhanced treatment efficacy.

Despite progress in cancer immunotherapy, ovarian cancer (OC) prognosis continues to be disappointing. Recent studies have shed light on how not just tumour cells, but also the complex tumour microenvironment, contribute to this unfavourable outcome of OC immunotherapy. The complexities of the immune microenvironment categorize OC as a 'cold tumour'. Nonetheless, understanding the precise mechanisms through which the microenvironment influences the effectiveness of OC immunotherapy remains an ongoing scientific endeavour. This review primarily aims to dissect the inherent characteristics and behaviours of diverse cells within the immune microenvironment, along with an exploration into its reprogramming and metabolic changes. It is expected that these insights will elucidate the operational dynamics of the immune microenvironment in OC and lay a theoretical groundwork for improving the efficacy of immunotherapy in OC management.

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.

RNA modifications in cancer.

Currently, more than 170 modifications have been identified on RNA. Among these RNA modifications, various methylations account for two-thirds of total cases and exist on almost all RNAs. Roles of RNA modifications in cancer are garnering increasing interest. The research on m6A RNA methylation in cancer is in full swing at present. However, there are still many other popular RNA modifications involved in the regulation of gene expression post-transcriptionally besides m6A RNA methylation. In this review, we focus on several important RNA modifications including m1A, m5C, m7G, 2'-O-Me, Ψ and A-to-I editing in cancer, which will provide a new perspective on tumourigenesis by peeking into the complex regulatory network of epigenetic RNA modifications, transcript processing, and protein translation.

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.

Adenosine diphosphate ribose cyclase: An important regulator of human pathological and physiological processes.

Adenosine diphosphate ribose cyclase (ADPRC) exists widely in eukaryotes and lower metazoans cells. It can degrade nicotinamide adenine dinucleotide (NAD) into cyclic ADP ribose (cADPR) and nicotinamide, and subsequently hydrolyses cADPR to ADP ribose (ADPR). In this paper, we have summarized the relative subcellular localization of ADPRC and enzymes with ADPRC activity in organisms, related enzyme family members of ADPRC are also described. In addition, we discussed the main biological functions of ADPRC, the regulation of Ca2+ signal, the regulation of insulin and glucagon secretion, oxytocin secretion, and the effects of renal and pulmonary vasomotor tension. Finally, we expounded the relationship between ADPRC and human health and disease occurrence. It provides a theoretical basis for the targeted treatment of ADPRC as a pharmacological tool for related diseases, and has important significance in clinical diagnosis and disease intervention.

Effect of CD38 on B-cell function and its role in the diagnosis and treatment of B-cell-related diseases.

CD38 is a multifunctional receptor and enzyme present on the surface of B lymphocytes, which can induce B lymphocytes proliferation and apoptosis by crosslinking related cytokines to affect the function of B cells, thus affecting immune regulation in humans and promoting tumorigenesis. The level of CD38 expression in B cells has become an important factor in the clinical diagnosis, treatment, and prognosis of malignant tumors and other related diseases. Therefore, studying the relationship between CD38 expression on the surface of B cells and the occurrence of the disease is of great significance for elucidating its association with disease pathogenesis and the clinical targeted therapy. In this paper, we review the effects of CD38 on B-cell activation, proliferation, and differentiation, and elaborate the functional role and mechanism of CD38 expression on B cells. We also summarize the relationship between the level of CD38 expression on the surface of B cells and the diagnosis, treatment, and prognosis of various diseases, as well as the potential use of targeted CD38 treatment for related diseases. This will provide an important theoretical basis for the scientific research and clinical diagnosis and treatment of B-cell-related diseases.

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.

Circular RNA circPVT1 promotes nasopharyngeal carcinoma metastasis via the ß-TrCP/c-Myc/SRSF1 positive feedback loop.

BACKGROUND: Circular RNAs (circRNAs) act as gene expression regulators and are involved in cancer progression. However, their functions have not been sufficiently investigated in nasopharyngeal carcinoma (NPC). METHODS: The expression profiles of circRNAs in NPC cells within different metastatic potential were reanalyzed. Quantitative reverse transcription PCR and in situ hybridization were used to detect the expression level of circPVT1 in NPC cells and tissue samples. The association of expression level of circPVT1 with clinical properties of NPC patients was evaluated. Then, the effects of circPVT1 expression on NPC metastasis were investigated by in vitro and in vivo functional experiments. RNA immunoprecipitation, pull-down assay and western blotting were performed to confirm the interaction between circPVT1 and ß-TrCP in NPC cells. Co-immunoprecipitation and western blotting were performed to confirm the interaction between ß-TrCP and c-Myc in NPC cells. RESULTS: We find that circPVT1, a circular RNA, is significantly upregulated in NPC cells and tissue specimens. In vitro and in vivo experiments showed that circPVT1 promotes the invasion and metastasis of NPC cells. Mechanistically, circPVT1 inhibits proteasomal degradation of c-Myc by binding to ß-TrCP, an E3 ubiquiting ligase. Stablization of c-Myc by circPVT1 alters the cytoskeleton remodeling and cell adhesion in NPC, which ultimately promotes the invasion and metastasis of NPC cells. Furthermore, c-Myc transcriptionally upregulates the expression of SRSF1, an RNA splicing factor, and recruits SRSF1 to enhance the biosynthesis of circPVT1 through coupling transcription with splicing, which forms a positive feedback for circPVT1 production. CONCLUSIONS: Our results revealed the important role of circPVT1 in the progression of NPC through the ß-TrCP/c-Myc/SRSF1 positive feedback loop, and circPVT1 may serve as a prognostic biomarker or therapeutic target in patients with NPC.

Oncogenic roles of the lncRNA LINC00460 in human cancers.

Long noncoding RNAs (lncRNAs) represent an important group of endogenous RNAs with limit protein-encoding capability, with a length of more than 200 nucleotides. Emerging evidence have demonstrated that lncRNAs are greatly involved in multiple cancers by playing critical roles in tumor initiation and progression. Long intergenic non-protein coding RNA 460 (LINC00460), a novel cancer-related lncRNA, exhibits abnormal expression and oncogenic function in multiple cancers, and positively correlates with poor clinical characteristics of cancer patients. LINC00460 has also been shown to be a promising biomarker for diagnosis as well as prognostic evaluation in cancer patients. In this review, we briefly summarized recent knowledge on the expression, functional roles, molecular mechanisms, and diagnostic and prognostic values of LINC00460 in human malignancies.

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.

Circular RNA circRNF13 inhibits proliferation and metastasis of nasopharyngeal carcinoma via SUMO2.

BACKGROUND: Circular RNAs (circRNAs) are widely expressed in human cells and are closely associated with cancer development. However, they have rarely been investigated in the context of nasopharyngeal carcinoma (NPC). METHODS: We screened a new circRNA, circRNF13, in NPC cells using next-generation sequencing of mRNA. Reverse transcription polymerase chain reaction and RNA fluorescence in situ hybridization were used to detect circRNF13 expression in 12 non-tumor nasopharyngeal epithelial (NPE) tissues and 36 NPC samples. Cell proliferation was detected using MTT and flow cytometry assays, and colony formation capability was detected using colony formation assays. Cell migration and invasion were analyzed using wound-healing and Transwell assays, respectively. Cell glycolysis was analyzed using the Seahorse glycolytic stress test. Glucose transporter type 1 (GLUT1) ubiquitination and SUMOylation modifications were analyzed using co-immunoprecipitation and western blotting. CircRNF13 and Small Ubiquitin-like Modifier 2 (SUMO2) interactions were analyzed using RNA pull-down and luciferase reporter assays. Finally, to test whether circRNF13 inhibited NPC proliferation and metastasis in vivo, we used a xenograft nude mouse model generated by means of subcutaneous or tail vein injection. RESULTS: We found that circRNF13 was stably expressed at low levels in NPC clinical tissues and NPC cells. In vitro and in vivo experiments showed that circRNF13 inhibited NPC proliferation and metastasis. Moreover, circRNF13 activated the SUMO2 protein by binding to the 3'- Untranslated Region (3'-UTR) of the SUMO2 gene and prolonging the half-life of SUMO2 mRNA. Upregulation of SUMO2 promotes GLUT1 degradation through SUMOylation and ubiquitination of GLUT1, which regulates the AMPK-mTOR pathway by inhibiting glycolysis, ultimately resulting in the proliferation and metastasis of NPC. CONCLUSIONS: Our results revealed that a novel circRNF13 plays an important role in the development of NPC through the circRNF13-SUMO2-GLUT1 axis. This study implies that circRNF13 mediates glycolysis in NPC by binding to SUMO2 and provides an important theoretical basis for further elucidating the pathogenesis of NPC and targeted therapy.

LncRNA GACAT3 promotes esophageal squamous cell carcinoma progression through regulation of miR-149/FOXM1.

BACKGROUND: The long noncoding RNA gastric cancer associated transcript 3 (GACAT3) has been demonstrated to be implicated in the carcinogenesis and progression of many malignancies. However, GACAT3's levels and role in esophageal squamous cell carcinoma (ESCC) has not been elucidated. METHODS: GACAT3 amounts were investigated in ESCC tissues and cell lines by qPCR. Its biological functions were examined by CCK-8 assay, colony formation assay, flow cytometry, wound healing assay, transwell assay, and xenograft model establishment. The relationship between GACAT3 and miR-149 was assessed by dual-luciferase reporter assay. RESULTS: GACAT3 amounts were elevated in ESCC tissue and cell specimens. Functional studies showed that GACAT3 silencing reduced the proliferation, migration and invasion of cultured ESCC cells, and decreased tumor growth in mice. Furthermore, GACAT could directly interact with miR-149. In addition, colony formation and invasion assays verified that GACAT3 promotes ESCC tumor progression through miR-149. Moreover, GACAT3 acted as a competing endogenous RNA (ceRNA) to modulate FOXM1 expression. CONCLUSIONS: These findings indicate that GACAT3 functions as an oncogene by acting as a ceRNA for miR-149 to modulate FOXM1 expression in ESCC, suggesting that GACAT3 might constitute a therapeutic target in ESCC.

EBV-miR-BART12 accelerates migration and invasion in EBV-associated cancer cells by targeting tubulin polymerization-promoting protein 1.

Epstein-Barr virus (EBV) infection leads to cancers with an epithelial origin, such as nasopharyngeal cancer and gastric cancer, as well as multiple blood cell-based malignant tumors, such as lymphoma. Interestingly, EBV is also the first virus found to carry genes encoding miRNAs. EBV encodes 25 types of pre-miRNAs which are finally processed into 44 mature miRNAs. Most EBV-encoded miRNAs were found to be involved in the occurrence and development of EBV-related tumors. However, the function of EBV-miR-BART12 remains unclear. The findings of the current study revealed that EBV-miR-BART12 binds to the 3'UTR region of Tubulin Polymerization-Promoting Protein 1 (TPPP1) mRNA and downregulates TPPP1, thereby promoting the invasion and migration of EBV-related cancers, such as nasopharyngeal cancer and gastric cancer. The mechanism underlying this process was found to be the inhibition of TPPP1 by EBV-miRNA-BART12, which, in turn, inhibits the acetylation of α-tubulin, and promotes the dynamic assembly of microtubules, remodels the cytoskeleton, and enhances the acetylation of ß-catenin. ß-catenin activates epithelial to mesenchymal transition (EMT). These two processes synergistically promote the invasion and metastasis of tumor cells. To the best of our knowledge, this is the first study to reveal the role of EBV-miRNA-BART12 in the development of EBV-related tumors as well as the mechanism underlying this process, and suggests potential targets and strategies for the treatment of EBV-related tumors.

Recent advances of fluorescent biosensors based on cyclic signal amplification technology in biomedical detection.

The cyclic signal amplification technology has been widely applied for the ultrasensitive detection of many important biomolecules, such as nucleic acids, proteins, enzymes, adenosine triphosphate (ATP), metal ions, exosome, etc. Due to their low content in the complex biological samples, traditional detection methods are insufficient to satisfy the requirements for monitoring those biomolecules. Therefore, effective and sensitive biosensors based on cyclic signal amplification technology are of great significance for the quick and simple diagnosis and treatment of diseases. Fluorescent biosensor based on cyclic signal amplification technology has become a research hotspot due to its simple operation, low cost, short time, high sensitivity and high specificity. This paper introduces several cyclic amplification methods, such as rolling circle amplification (RCA), strand displacement reactions (SDR) and enzyme-assisted amplification (EAA), and summarizes the research progress of using this technology in the detection of different biomolecules in recent years, in order to provide help for the research of more efficient and sensitive detection methods.