[Aucubin combined with ADSCs-exos protects TBHP-induced nucleus pulposus cells via TLR4/NF-κB pathway].

This paper aims to investigate the effects and mechanisms of adipose-derived stem cells-exosomes(ADSCs-exos) toge-ther with aucubin in protecting human-derived nucleus pulposus cells(NPCs) from inflammatory injury, senescence, and apoptosis. The tert-butyl hydroperoxide(TBHP)-induced NPCs were assigned into normal, model, aucubin, ADSCs-exos, and aucubin+ADSCs-exos groups. The cell viability was examined by cell counting kit-8(CCK-8), cell proliferation by EdU staining, cell senescence by senescence-associated-ß-galactosidase(SA-ß-Gal), and cell cycle and apoptosis by flow cytometry. Enzyme-linked immunosorbent assay was employed to examine the expression of interleukin-1ß(IL-1ß), IL-10, and tumor necrosis factor-α(TNF-α). Real-time fluorescence quantitative PCR and Western blot were employed to determine the mRNA and protein levels of aggregated proteoglycan(aggrecan), type Ⅱ collagen alpha 1(COL2A1), Toll-like receptor 4(TLR4), and nuclear factor-kappa B(NF-κB). The results showed that compared with the model group, the aucubin or ADSCs-exos group showed enhanced viability and proliferation of NPCs, decreased proportion of G_0/G_1 phase cells, increased proportion of S phase cells, reduced apoptosis and proportion of cells in senescence, lowered IL-1ß and TNF-α levels, elevated IL-10 level, down-regulated mRNA and protein levels of TLR4 and NF-κB, and up-regulated mRNA and protein levels of aggrecan and COL2A1. Compared with the aucubin or ADSCs-exos group, the aucubin+ADSCs-exos combination further increased the viability and proliferation of NPCs, decreased the proportion of G_0/G_1 phase cells, increased the proportion of S phase cells, reduced the apoptosis and proportion of cells in senescence, lowered the IL-1ß and TNF-α levels, elevated the IL-10 level, down-regulated the mRNA and protein levels of TLR4 and NF-κB, and up-regulated the mRNA and protein levels of aggrecan and COL2A1. In summary, both aucubin and ADSCs-exos could exert protective effects by inhibiting inflammatory responses, reducing apoptosis and senescence of NPCs, improving cell viability and proliferation as well as extracellular matrix synthesis, which may be associated with the inhibition of TLR4/NF-κB signaling pathway activation. The combination of both plays a synergistic role in the protective effects.

Psoralen synergizes with exosome-loaded SPC25 to alleviate senescence of nucleus pulposus cells in intervertebral disc degeneration.

OBJECTIVE: To explore the mechanism of psoralen synergized with exosomes (exos)-loaded SPC25 on nucleus pulposus (NP) cell senescence in intervertebral disc degeneration (IVDD). METHODS: IVDD cellular models were established on NP cells by tert-butyl hydroperoxide (TBHP) induction, followed by the treatment of psoralen or/and exos from adipose-derived stem cells (ADSCs) transfected with SPC25 overexpression vector (ADSCs-oe-SPC25-Exos). The viability, cell cycle, apoptosis, and senescence of NP cells were examined, accompanied by the expression measurement of aggrecan, COL2A1, Bcl-2, Bax, CDK2, p16, and p21. RESULTS: After TBHP-induced NP cells were treated with psoralen or ADSCs-oe-SPC25-Exos, cell proliferation and the expression of aggrecan, COL2A1, Bcl-2, and CDK2 were promoted; however, the expression of Bax, p16, p21, and inflammatory factors was decreased, and cell senescence, cycle arrest, and apoptosis were inhibited. Of note, psoralen combined with ADSCs-oe-SPC25-Exos further decelerated NP cell senescence and cycle arrest compared to psoralen or ADSCs-oe-SPC25-Exos alone. CONCLUSION: Combined treatment of psoralen and ADSCs-oe-SPC25-Exos exerted an alleviating effect on NP cell senescence, which may provide an insightful idea for IVDD treatment.

BSHXF-medicated serum combined with ADSCs regulates the TGF-ß1/Smad pathway to repair oxidatively damaged NPCs and its component analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Lower back pain (LBP) is a common and frequent clinical condition, and intervertebral disc degeneration (IDD) is recognized as the leading cause of LBP, typically manifested by increased nucleus pulposus cell (NPC) senescence and death. In recent years, the treatment of IDD with stem cell injections has had great potential compared to surgical treatment. Combining the two may achieve better results, as BuShenHuoXueFang (BSHXF) is an herbal formula that improves the survival rate of transplanted stem cells and enhances their efficacy. AIM OF THE STUDY: We aimed to qualitatively and quantitatively analyze BSHXF-medicated serum and investigate the molecular mechanism of BSHXF-mediated serum in promoting the differentiation of adipose mesenchymal stem cells (ADSCs) into NPCs and delaying the senescence of NPCs by regulating the TGF-ß1/Smad pathway. MATERIALS AND METHODS: In this study, an ultrahigh-performance liquid chromatography-quadrupole-time-of-flight mass spectrometer (UPLC-Q-TOF-MS) was used to establish a method for the analysis of rat serum samples to track the active components in vivo; the oxidative damage model of NPCs was induced by T-BHP, and a Transwell chamber was used to construct a coculture system of ADSCs and NPCs. Flow cytometry was used to determine the cell cycle; SA-ß-Gal staining was used to assess cell senescence; ELISA was used to detect IL-1ß, IL-6 inflammatory factors, CXCL-1, CXCL-3, CXCL-10 chemokines, and TGF-ß1 in the supernatants of ADSCs and NPCs. WB was used to detect COL2A1, COL1A1, and Aggrecan in ADSCs to assess the manifestation of NP differentiation in ADSCs, and the WB method was used to detect COL2A1, COL1A1, Aggrecan, p16, p21, p53, and p-p53 protein expression in NPCs to reflect the cellular senescence status and to detect TGF-ß1, Smad2, Smad3, p- Smad2, and p- Smad3 protein expression in NPCs to reflect the pathway condition. RESULTS: We finally identified 70 blood components and their metabolites, including 38 prototypes, from the BSHXF-medicated serum. Compared with that in the nonmedicated serum group, the TGF-ß1/Smad pathway was activated in the medicated serum group, ADSCs moved toward NPC characteristics, the number of NPCs in the S/G2M phase increased, the number of senescent NPCs decreased, IL-1ß and IL-6 inflammatory factors in the Transwell decreased, CXCL-1, CXCL-3, and CXCL-10 chemokines decreased, and the expression of p16, p21, p53 and p-p53 proteins in NPCs was inhibited. CONCLUSION: By regulating the TGF-ß1/Smad pathway, BSHXF-medicated serum promoted ADSCs to NPCs, effectively alleviated the cycle blockage of NPCs after oxidative damage, encouraged the growth and proliferation of NPCs, delayed the aging of NPCs, improved the deteriorating microenvironment around NPCs, and repaired oxidatively damaged NPCs. The combination of BSHXF or its compounds with ADSCs has great potential for the treatment of IDD in the future.

Geniposide ameliorates atherosclerosis by regulating macrophage polarization via perivascular adipocyte-derived CXCL14.

ETHNOPHARMACOLOGICAL RELEVANCE: Gardenia jasminoides Ellis is a traditional Chinese medicine that has been used for treatment of various diseases, including atherosclerosis by clearing heat and detoxication. Geniposide is considered as the effective compounds responsible for the therapeutic efficacy of Gardenia jasminoides Ellis against atherosclerosis. AIM OF THE STUDY: To investigate the effect of geniposide on atherosclerosis burden and plaque macrophage polarization, with focus on its potential impact on CXCL14 expression by perivascular adipose tissue (PVAT). MATERIALS AND METHODS: ApoE-/- mice fed a western diet (WD) were used to model atherosclerosis. In vitro cultures of mouse 3T3-L1 preadipocytes and RAW264.7 macrophages were used for molecular assays. RESULTS: The results revealed that geniposide treatment reduced atherosclerotic lesions in ApoE-/- mice, and this effect was correlated with increased M2 and decreased M1 polarization of plaque macrophages. Of note, geniposide increased the expression of CXCL14 in PVAT, and both the anti-atherosclerotic effect of geniposide, as well as its regulatory influence on macrophage polarization, were abrogated upon in vivo CXCL14 knockdown. In line with these findings, exposure to conditioned medium from geniposide-treated 3T3-L1 adipocytes (or to recombinant CXCL14 protein) enhanced M2 polarization in interleukin-4 (IL-4) treated RAW264.7 macrophages, and this effect was negated after CXCL14 silencing in 3T3-L1 cells. CONCLUSION: In summary, our findings suggest that geniposide protects ApoE-/- mice against WD-induced atherosclerosis by inducing M2 polarization of plaque macrophages via enhanced expression of CXCL14 in PVAT. These data provide novel insights into PVAT paracrine function in atherosclerosis and reaffirm geniposide as a therapeutic drug candidate for atherosclerosis treatment.

Psoralidin Induced Differentiation from Adipose-derived Stem Cells to Nucleus Pulposus-like Cells by TGF-ß/Smad Signaling.

BACKGROUND: Psoralidin (PL) could affect the differentiation of bone marrow mesenchymal stem cells (BMSCs). The role of PL is still unclear in adipose-derived stem cells (ADSCs). AIMS: This study aimed to investigate the effects of PL on ADSCs differentiation into nucleus pulposus-like cells and the TGF-ß/Smad signaling pathway. METHODS: The proliferation and apoptosis of ADSCs were detected. The nucleus pulposus cell-related markers (CD24, BASP1, KRT19, and Aggrecan) and TGF-ß/Smad signaling pathway indexes were analyzed. RESULTS: The results showed that compared to the control group, the cell activity was increased in the PL group, and the apoptosis rate was decreased. The mRNA and protein levels of nucleus pulposus cells markers (CD24, BASP1, KRT19, Aggrecan, and Collagen Type II) and TGF-ß/Smad signaling pathway-related indexes (TGF-ß, SMAD2, and SMAD3) were increased in PL group. After treatment with PL and TGF-ß silencing, the TGF-ß/Smad signaling pathway-related indicators (TGF-ß, SMAD2, and SMAD3) and nucleus pulposus cells markers (CD24, BASP1, KRT19, Aggrecan, and Collagen Type II) were found to be higher in the sh-TGF-ß +PL group than in the sh-TGF-ß group. CONCLUSION: In conclusion, our study showed that PL might induce the differentiation of ADSCs to nucleus pulposus cells through the TGF-ß/Smad signaling pathway. It might have the potential application value in the treatment of intervertebral disc degeneration.

Achyranthoside D (AD) improve intervertebral disc degeneration through affect the autophagy and the activation of PI3K/Akt/mTOR pathway.

PURPOSE: This study aims to explore the potential mechanism of Achyranthoside D (AD) in improving intervertebral disc (IVD) degeneration (IDD). METHODS: The IDD model of SD rats and nucleus pulposus cells (NPCs) was established by lumbar cone annulus puncture and tert-butyl peroxide, respectively. Cell proliferation was detected by CCK8 assay. Apoptosis was detected by flow cytometry and TUNEL staining. IVD tissue injury was observed by HE staining. Alcian blue staining observed the glycoprotein secretion in IVD. Monodansylcadaverin (MDC) staining was used to detect the formation of autophagosomes. The LC3 expression was tested by immunofluorescence. The type II collagen, aggrecan and MMP3 expression were detected by ELISA. RT-qPCR was used to detect the Casp 3, Bax, Bcl2, Acan, Col2a1 and Mmp3 expression. The LC3, P62, type II collagen, aggrecan, Beclin1, Akt, MMP3, p-mTOR, PI3K, mTOR, p-PI3K and p-Akt expression were analyzed by western blot. RESULTS: The IVD tissue damage and apoptosis occurred in the Model group, and the glycoprotein secretion decreased. Compared with Model group, AD-H group alleviated the injury of IVD tissue, inhibited the apoptosis of cells, and increased the secretion of glycoprotein. 40 µg/mL AD restored the proliferation activity of NPCs. Compared to the Normal group, the NPCs apoptosis increased, the Collagen II, aggrecan and Bcl2 expressions were significantly decreased, the MMP3, Bax and Casp 3 expression were significantly increased, and the LC-3 II/I expression in IVD tissues were increased significantly in Model group, all of which was reversed in AD group. AD promoted the p-Akt, p-PI3K, p-mTOR, LC-3 II/I and Beclin1 expression, inhibited the P62 expression to alleviate the damage of nucleus pulporeus cells and the degeneration of IVD. CONCLUSION: AD improved IDD by affecting the PI3K/Akt/mTOR pathway and autophagy.

Construction and validation of a prognostic model with RNA binding protein-related mRNAs for the HBV-related hepatocellular carcinoma patients.

Hepatocellular carcinoma (HCC) is a common malignancy worldwide with poor clinical outcomes, and the infection of hepatitis B virus (HBV) is the leading cause of this disease. Mounting evidence shows that RNA binding proteins (RBPs) can modulate the progression of cancers. However, the functions and clinical implications of RBP-related mRNAs in HBV-related HCC remain largely unclear. Therefore, we aim to develop a prognostic model based on the RBP-related mRNAs for HBV-related HCC patients. Firstly, we identified 626 differentially expressed RBP-related mRNAs in the HBV-related HCC through the Pearson correlation analysis. Subsequently, the Kaplan-Meier survival, univariate, Least Absolute Shrinkage and Selection Operator (LASSO), and multivariate Cox regression analyses were used to construct a prognostic model comprised of five RBP-related mRNAs. Furthermore, the patients were categorized into the high- and low-risk groups by the prognostic model and the patients in the high-risk group had a poor prognosis. Additionally, the prognostic model was an independent predictor of prognosis, and the accuracy of the prognostic model was proved by the receiver operator characteristic (ROC) analysis. Furthermore, the functional enrichment analysis revealed that various cancer-promoting processes were enriched in the high-risk group. Taken together, our study may provide the HBV-related HCC biomarkers of prognosis to improve the clinical outcomes of patients.

Integrated Analysis of a Ferroptosis-Related LncRNA Signature for Evaluating the Prognosis of Patients with Colorectal Cancer.

LncRNAs have been well known for their multiple functions in the tumorigenesis, development, and relapse of colorectal cancer (CRC). Accumulating studies demonstrated that the expression of lncRNAs can be regulated by ferroptosis, a biological process that has been revealed to suppress CRC progression. However, the functions and clinical implications of ferroptosis-associated lncRNAs in CRC remain largely unknown. We, herein, aim to construct a prognostic signature with ferroptosis-related lncRNAs for the prognostic estimation of CRC patients. Firstly, we identified the lncRNAs related to ferroptosis based on the RNA-Seq data of CRC from the TCGA database. The univariate and multivariate Cox analyses were then performed to establish a prognostic signature composed of eight ferroptosis-related lncRNAs (AL161729.4, AC010973.2, CCDC144NL-AS1, AC009549.1, LINC01857, AP003555.1, AC099850.3, and AC008494.3). Furthermore, we divided the CRC patients into high- and low-risk groups based on the signature and found the overall survival (OS) of patients in the high-risk group was significantly shorter than that in the low-risk group (p = 3.31 × 10-11). Moreover, the patients in the high-risk groups had shorter recurrence-free survival (RFS) (p = 6.5 × 10-3) and disease-free survival (DFS) (p = 4.27 × 10-4), as well as higher tumor recurrence rate. Additionally, we found that the oncogenic pathways were enriched in the high-risk group, whereas the ferroptosis pathway that probably repressed CRC development was enriched in the low-risk group. In summary, our signature may provide a theoretical foundation for not only accurate judgment for prognosis but also evaluation for recurrence and metastasis in CRC patients.

Multi-Modal Optical Imaging and Combined Phototherapy of Nasopharyngeal Carcinoma Based on a Nanoplatform.

Nasopharyngeal carcinoma (NPC) is a common malignant tumor of the head and neck with a high incidence rate worldwide, especially in southern China. Phototheranostics in combination with nanoparticles is an integrated strategy for enabling simultaneous diagnosis, real-time monitoring, and administration of precision therapy for nasopharyngeal carcinoma (NPC). It has shown great potential in the field of cancer diagnosis and treatment owing to its unique noninvasive advantages. Many Chinese and international research teams have applied nano-targeted drugs to optical diagnosis and treatment technology to conduct multimodal imaging and collaborative treatment of NPC, which has become a hot research topic. In this review, we aimed to introduce the recent developments in phototheranostics of NPC based on a nanoplatform. This study aimed to elaborate on the applications of nanoplatform-based optical imaging strategies and treatment modalities, including fluorescence imaging, photoacoustic imaging, Raman spectroscopy imaging, photodynamic therapy, and photothermal therapy. This study is expected to provide a scientific basis for further research and development of NPC diagnosis and treatment.

Integrated Analysis of RNA Binding Protein-Related lncRNA Prognostic Signature for Breast Cancer Patients.

Long non-coding RNAs (lncRNAs) have been well known for their multiple functions in the tumorigenesis, development, and prognosis of breast cancer (BC). Mechanistically, their production, function, or stability can be regulated by RNA binding proteins (RBPs), which were also involved in the carcinogenesis and progression of BC. However, the roles and clinical implications of RBP-related lncRNAs in BC remain largely unknown. Therefore, we herein aim to construct a prognostic signature with RBP-relevant lncRNAs for the prognostic evaluation of BC patients. Firstly, based on the RNA sequencing data of female BC patients from The Cancer Genome Atlas (TCGA) database, we screened out 377 differentially expressed lncRNAs related to RBPs. The univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses were then performed to establish a prognostic signature composed of 12-RBP-related lncRNAs. Furthermore, we divided the BC patients into high- and low-risk groups by the prognostic signature and found the overall survival (OS) of patients in the high-risk group was significantly shorter than that of the low-risk group. Moreover, the 12-lncRNA signature exhibited independence in evaluating the prognosis of BC patients. Additionally, a functional enrichment analysis revealed that the prognostic signature was associated with some cancer-relevant pathways, including cell cycle and immunity. In summary, our 12-lncRNA signature may provide a theoretical reference for the prognostic evaluation or clinical treatment of BC patients.

Guidance of circular RNAs to proteins' behavior as binding partners.

Circular RNAs (circRNAs) are single-stranded and covalently closed back-splicing products of pre-mRNAs. They can be derived from exons, introns, or exons with intron retained between exons of transcripts, as well as antisense transcripts. CircRNAs have been reported to function as microRNA sponges, regulate gene transcription mediated by RNA polymerase II, and modulate the splicing or stability of mRNA. However, emerging studies demonstrate that they affect the behavior of proteins via direct interactions with them. Here, we summarize that by binding directly with proteins; circRNAs can facilitate their nuclear or cytoplasmic localizations, regulate their functions or stability, promote or inhibit the interactions between them, or influence the interactions between them and DNA. Furthermore, these circRNA-binding proteins contain transcription factors, RNA processing proteins, proteases, and some other RNA-binding proteins. As a consequence, circRNAs are involved in the regulation of multiple physiological or pathological processes, including tumorigenesis, atherosclerosis, wound repair, cardiac senescence, myocardial ischemia/reperfusion injury, and so forth. Nonetheless, it is worthwhile to further explore more types of proteins that interact with circRNAs, which would be helpful in revealing other unknown biological functions of circRNAs that guide the variation in behavior of cellular proteins.

DIS3L2 Promotes Progression of Hepatocellular Carcinoma via hnRNP U-Mediated Alternative Splicing.

DIS3-like 3'-5' exoribonuclease 2 (DIS3L2) degrades aberrant RNAs, however, its function in tumorigenesis remains largely unexplored. Here, aberrant DIS3L2 expression promoted human hepatocellular carcinoma (HCC) progression via heterogeneous nuclear ribonucleoproteins (hnRNP) U-mediated alternative splicing. DIS3L2 directly interacted with hnRNP U through its cold-shock domains and promoted inclusion of exon 3b during splicing of pre-Rac1 independent of its exonuclease activity, yielding an oncogenic splicing variant, Rac1b, which is known to stimulate cellular transformation and tumorigenesis. DIS3L2 regulated alternative splicing by recruiting hnRNP U to pre-Rac1. Rac1b was critical for DIS3L2 promotion of liver cancer development both in vitro and in vivo. Importantly, DIS3L2 and Rac1b expression highly correlated with HCC progression and patient survival. Taken together, our findings uncover an oncogenic role of DIS3L2, in which it promotes liver cancer progression through a previously unappreciated mechanism of regulating hnRNP U-mediated alterative splicing. SIGNIFICANCE: These findings establish the role and mechanism of the 3'-5' exoribonuclease DIS3L2 in hepatocellular carcinoma carcinogenesis.

Aucubin inhibits IL-1ß- or TNF-α-induced extracellular matrix degradation in nucleus pulposus cell through blocking the miR-140-5p/CREB1 axis.

In intervertebral disc degeneration (IDD), increased proinflammatory molecules secreted by human nucleus pulposus cells (HNPCs) could promote the expression of extracellular matrix (ECM)-degrading enzymes. IDD could be affected by both genetic and environmental factors, including microRNAs (miRNAs). Aucubin, the active ingredient of a traditional Chinese medicine herb Du Zhong, has been reported to promote osteogenic differentiation; however, the role of aucubin in IDD and the underlying mechanism remain unclear. Herein, we evaluated the effect of aucubin on TNF-α- or IL-1ß-induced ECM degradation in HNPCs. By using online tools, miR-140 was selected as a candidate miRNA that is related to TNF-α or IL-1ß signaling. Overexpression of miR-140 enhanced the effect of aucubin on ECM degradation. Moreover, cAMP responsive element binding protein 1 (CREB1), a major transcriptional factor in immune-related signaling, was a direct downstream target of miR-140. CREB1 knockdown mimicked the function of miR-140 overexpression on ECM degradation. In summary, aucubin might ameliorate IL-1ß- or TNF-α-induced ECM degradation in HNPCs through regulating miR-140/CREB1.

Regulation of RNA decay and cellular function by 3'-5' exoribonuclease DIS3L2.

DIS3L2, in which mutations have been linked to Perlman syndrome, is an RNA-binding protein with 3'-5' exoribonuclease activity. It contains two CSD domains and one S1 domain, all of which are RNA-binding domains, and one RNB domain that is responsible for the exoribonuclease activity. The 3' polyuridine of RNA substrates can serve as a degradation signal for DIS3L2. Because DIS3L2 is predominantly localized in the cytoplasm, it can recognize, bind, and mediate the degradation of cytoplasmic uridylated RNA, including pre-microRNA, mature microRNA, mRNA, and some other non-coding RNAs. Therefore, DIS3L2 plays an important role in cytoplasmic RNA surveillance and decay. DIS3L2 is involved in multiple biological and physiological processes such as cell division, proliferation, differentiation, and apoptosis. Nonetheless, the function of DIS3L2, especially its association with cancer, remains largely unknown. We summarize here the RNA substrates degraded by DIS3L2 with its exonucleolytic activity, together with the corresponding biological functions it is implicated in. Furthermore, we discuss whether DIS3L2 can function independently of its 3'-5' exoribonuclease activity, as well as its potential tumor-suppressive or oncogenic roles during cancer progression.

Long non-coding RNAs involved in cancer metabolic reprogramming.

Metabolic reprogramming has now been accepted as a hallmark of cancer. Compared to normal cells, cancer cells exhibit different metabolic features, including increased glucose uptake, aerobic glycolysis, enhanced glutamine uptake and glutaminolysis, altered lipid metabolism, and so on. Cancer metabolic reprogramming, which supports excessive cell proliferation and growth, has been widely regulated by activation of oncogenes or loss of tumor suppressors. Here, we review that long non-coding RNAs (lncRNAs) can affect cancer metabolism by mutual regulation with oncogenes or tumor suppressors. Additionally, the interaction of lncRNAs with crucial transcription factors, metabolic enzymes or microRNAs can also effectively modulate the processes of cancer metabolism. LncRNAs-derived metabolism reprogramming allows cancer cells to maintain deregulated proliferation and withstand hostile microenvironment such as energy stress. Understanding the functions of lncRNAs in cancer metabolic reprogramming that contributes to carcinogenesis and cancer development may help to develop novel and effective strategies for cancer diagnosis, prognosis and treatment.

Aberrant Regulation of mRNA m6A Modification in Cancer Development.

N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic messenger RNAs (mRNAs). The m6A modification in RNA can be catalyzed by methyltransferases, or removed by demethylases, which are termed m6A writers and erasers, respectively. Selective recognition and binding by distinct m6A reader proteins lead mRNA to divergent destinies. m6A has been reported to influence almost every stage of mRNA metabolism and to regulate multiple biological processes. Accumulating evidence strongly supports the correlation between aberrant cellular m6A level and cancer. We summarize here that deregulation of m6A modification, resulting from aberrant expression or function of m6A writers, erasers, readers or some other protein factors, is associated with carcinogenesis and cancer progression. Understanding the regulation and functional mechanism of mRNA m6A modification in cancer development may help in developing novel and efficient strategies for the diagnosis, prognosis and treatment of human cancers.

Author Correction: Menin enhances c-Myc-mediated transcription to promote cancer progression.

This corrects the article DOI: 10.1038/ncomms15278.

Menin enhances c-Myc-mediated transcription to promote cancer progression.

Menin is an enigmatic protein that displays unique ability to either suppress or promote tumorigenesis in a context-dependent manner. The role for Menin to promote oncogenic functions has been largely attributed to its essential role in forming the MLL methyltransferase complex, which mediates H3K4me3. Here, we identify an unexpected role of Menin in enhancing the transactivity of oncogene MYC in a way independent of H3K4me3 activity. Intriguingly, we find that Menin interacts directly with the TAD domain of MYC and co-localizes with MYC to E-Box to enhance the transcription of MYC target genes in a P-TEFb-dependent manner. We further demonstrate that, by transcriptionally promoting the expression of MYC target genes in cancer cells, Menin stimulates cell proliferation and cellular metabolism both in vitro and in vivo. Our results uncover a previously unappreciated mechanism by which Menin functions as an oncogenic regulatory factor that is critical for MYC-mediated gene transcription.

CUE domain-containing protein 2 promotes the Warburg effect and tumorigenesis.

Cancer progression depends on cellular metabolic reprogramming as both direct and indirect consequence of oncogenic lesions; however, the underlying mechanisms are still poorly understood. Here, we report that CUEDC2 (CUE domain-containing protein 2) plays a vital role in facilitating aerobic glycolysis, or Warburg effect, in cancer cells. Mechanistically, we show that CUEDC2 upregulates the two key glycolytic proteins GLUT3 and LDHA via interacting with the glucocorticoid receptor (GR) or 14-3-3ζ, respectively. We further demonstrate that enhanced aerobic glycolysis is essential for the role of CUEDC2 to drive cancer progression. Moreover, using tissue microarray analysis, we show a correlation between the aberrant expression of CUEDC2, and GLUT3 and LDHA in clinical HCC samples, further demonstrating a link between CUEDC2 and the Warburg effect during cancer development. Taken together, our findings reveal a previously unappreciated function of CUEDC2 in cancer cell metabolism and tumorigenesis, illustrating how close oncogenic lesions are intertwined with metabolic alterations promoting cancer progression.

Noncoding RNAs in Regulation of Cancer Metabolic Reprogramming.

Since the description of the Warburg effect 90 years ago, metabolic reprogramming has been gradually recognized as a major hallmark of cancer cells. Mounting evidence now indicates that cancer is a kind of metabolic disease, quite distinct from conventional perception. While metabolic alterations in cancer cells have been extensively observed in glucose, lipid, and amino acid metabolisms, its underlying regulatory mechanisms are still poorly understood. Noncoding RNA, also known as the "dark matter in life," functions through various mechanisms at RNA level regulating different biological pathways. The last two decades have witnessed the booming of noncoding RNA study on microRNA (miRNA), long noncoding RNA (lncRNA), circular RNA (circRNA), PIWI-interacting RNA (piRNA), etc. In this chapter, we will discuss the regulatory roles of noncoding RNAs on cancer metabolism.