Polypyrimidine tract-binding protein 3/insulin-like growth factor 2 mRNA-binding proteins 3/high-mobility group A1 axis promotes renal cancer growth and metastasis.

Polypyrimidine tract-binding protein 3 (PTBP3) plays an important role in the post-transcriptional regulation of gene expression, including mRNA splicing, translation, and stability. Increasing evidence has shown that PTBP3 promotes cancer progression in several tumor types. However, the molecular mechanisms of PTBP3 in renal cell carcinoma (RCC) remain unknown. Here, tissue microarrays (TMAs) suggested that PTBP3 expression was increased in human RCC and that high PTBP3 expression was correlated with poor five-year overall survival and disease-free survival. We also showed that PTBP3 binds with HMGA1 mRNA in the 3'UTR region and let-7 miRNAs. PTBP3 interacted with IGF2BP3, and the PTBP3/IGF2BP3 axis prevented let-7 mediated HMGA1 mRNA silencing. PTBP3 promotes renal cancer cell growth and metastasis in vitro and in vivo. Taken together, our findings indicate PTBP3 serves as a regulator of HMGA1 and suggest its potential as a therapeutic agent for RCC.

circEPB41L2 blocks the progression and metastasis in non-small cell lung cancer by promoting TRIP12-triggered PTBP1 ubiquitylation.

The metastasis of non-small cell lung cancer (NSCLC) is the leading death cause of NSCLC patients, which requires new biomarkers for precise diagnosis and treatment. Circular RNAs (circRNAs), the novel noncoding RNA, participate in the progression of various cancers as microRNA or protein sponges. We revealed the mechanism by which circEPB41L2 (hsa_circ_0077837) blocks the aerobic glycolysis, progression and metastasis of NSCLC through modulating protein metabolism of PTBP1 by the E3 ubiquitin ligase TRIP12. With ribosomal RNA-depleted RNA seq, 57 upregulated and 327 downregulated circRNAs were identified in LUAD tissues. circEPB41L2 was selected due to its dramatically reduced levels in NSCLC tissues and NSCLC cells. Interestingly, circEPB41L2 blocked glucose uptake, lactate production, NSCLC cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, acting as a scaffold, circEPB41L2 bound to the RRM1 domain of the PTBP1 and the E3 ubiquitin ligase TRIP12 to promote TRIP12-mediated PTBP1 polyubiquitylation and degradation, which could be reversed by the HECT domain mutation of TRIP12 and circEPB41L2 depletion. As a result, circEPB41L2-induced PTBP1 inhibition led to PTBP1-induced PKM2 and Vimentin activation but PKM1 and E-cadherin inactivation. These findings highlight the circEPB41L2-dependent mechanism that modulates the "Warburg Effect" and EMT to inhibit NSCLC development and metastasis, offering an inhibitory target for NSCLC treatment.

MRI Directed Magnevist Effective to Study Toxicity of Gd-Doped Mesoporous Carbon Nanoparticles in Mice Model.

Purpose: Magnetic resonance imaging (MRI) has been a valuable and widely used examination technique in clinical diagnosis and prognostic efficacy evaluation. The introduction of MRI contrast agent (CA) improves its sensitivity obviously, particularly with the development of nano-CA, which presents higher contrast enhancement ability. However, systematical evaluation of their toxicity is still limited, hampering their further translation in clinics. Methods: In this paper, to systematically evaluate the toxicity of nano-CA, Gd-doped mesoporous carbon nanoparticles (Gd-MCNs) prepared by a one-step hard template method were introduced as a model and clinically used MRI CA, Magnevist (Gd-DTPA) as control. Their in vitro blood compatibility, cellular toxicity, DNA damage, oxidative stress, inflammation response as well as in vivo toxicity and MR imaging behaviors were studied and compared. Results: The experimental results showed that compared with Gd-DTPA, Gd-MCNs displayed negligible influence on the red blood cell shape, aggregation, BSA structure, macrophage morphology and mitochondrial function. Meanwhile, limited ROS and inflammatory cytokine production also illustrated the cellular compatibility of Gd-MCNs. For in vivo toxicity evaluation, Gd-MCNs presented acceptable in vivo biosafety even under 12 times injection for 12 weeks. More importantly, at the same concentration of Gd, Gd-MCNs displayed better contrast enhancement of tumor than Gd-DTPA, mainly coming from its high MRI relaxation rate which is nearly 9 times that of Gd-DTPA. Conclusion: In this paper, we focus on the toxicity evaluation of MRI nano-CA, Gd-MCNs from different angles. With Gd-DTPA as control, Gd-MCNs appeared to be highly biocompatible and safe nanoparticles that possessed promising potentials for the use of MRI nano-CA. In the future, more research on the long-term genotoxicity and the fate of nanoparticles after being swallowed should be performed.

The role of transcription factor Yin Yang-1 in colorectal cancer.

BACKGROUND: Yin Yang-1 (YY1) is identified as a transcription factor with multiple functions. However, the role of YY1 in tumorigenesis remains controversial and its regulatory effects may depend upon not only cancer types, but also its interacting partners, chromatin structure, and the context in which it acts. It has been detected that YY1 was highly expressed in colorectal cancer (CRC). Intriguingly, many YY1-repressed genes exhibit tumor suppressive potential while YY1 silencing is related to chemotherapy resistance. Therefore, it is crucial to meticulously explore YY1 protein structure and the dynamic alteration of its interactome in each cancer type. This review attempts to describe the structure of YY1, summarize the mechanism that influence the expression level of YY1 and also highlight the recent advances in our understanding of regulatory insights of YY1 functions in CRC. METHODS: Related studies were identified through scoping search of PubMed, Web of science, Scopus and Emhase concerning the terms of "colorectal cancer", colorectal carcinoma" or CRC with "YY1". The retrieval strategy included title, abstract, and keywords with no language limitations. All the included articles were categorized depending on the mechanisms they explored. RESULTS: In total, 170 articles were identified for further screening. After removing the duplication, not relevant outcomes and review articles, 34 were finally included in the review. Among them, 10 articles revealed the reasons of YY1 high expression in CRC, 13 articles explored YY1 function in CRC, and 11 articles fell into both aspects. In addition, we also summarized 10 clinical trials concerning the expression and activity of YY1 in various diseases, which offers a hint for future application. CONCLUSIONS: YY1 is highly expressed in CRC and broadly recognized as an oncogenic factor during the whole course of CRC. Sporadic controversial views are raised in term of CRC treatment, reminding us that future studies should take the influence of therapeutic regimens into concern.

[Retracted] Pin2/TRF1­binding protein X1 inhibits colorectal cancer cell migration and invasion in vitro and metastasis in vivo via the nuclear factor­κB signaling pathway.

Following the publication of the above article, an interested reader drew to the authors' attention that Figs. 3C and E in the paper appeared to contain instances of duplicated data. The authors were able to consult their original data files, and realized that these figures had indeed been assembled incorrectly; subsequently, they requested that a corrigendum be published to take account of the errors that were made during the compilation of these figures. Having investigated this matter in the Editorial Office, however, additional panels of overlapping data were identified, comparing between Figs. 3 and 5; specifically, overlapping data panels were also identified in panels in Figs. 3C, E and F, and 5C and D. The Editor of Oncology Reports has considered the authors' request to publish a corrigendum, but has decided to decline this request on account of the large number of errors that have been identified; rather, the article is to be be retracted from the Journal on the basis of an overall lack of confidence in the presented data. The Editor apologizes to the readership of the Journal for any inconvenience caused. [Oncology Reports 40: 1533­1544, 2018; DOI: 10.3892/or.2018.6570].

TRIM21 attenuates renal carcinoma lipogenesis and malignancy by regulating SREBF1 protein stability.

BACKGROUND: Metabolic reprogramming is a hallmark of various cancers. Targeting metabolic processes is a very attractive treatment for cancer. Renal cell carcinoma (RCC) is a type of metabolic disease, and the lipidomic profile of RCC is significantly altered compared with that of healthy tissue. However, the molecular mechanism underlying lipid metabolism regulation in RCC is not clear. METHODS: The XF long-chain fatty acid oxidative stress test kits were used to assess the dependence on long-chain fatty acids and mitochondrial function after knockdown TRIM21 in RCC cells. The effect of TRIM21 on the lipid content in RCC cells was determined by metabolomics analysis, Oil Red O staining, and cellular Nile red staining. qRT-PCR and western blot were used to explore the relationship between TRIM21 and lipogenesis, and then the key molecule sterol regulatory element binding transcription factor 1 (SREBF1) was identified to interact with TRIM21 by immunoprecipitation, which was also identified in an orthotopic model. Subsequently, the relevance and clinical significance of TRIM21 and SREBF1 were analyzed by The Cancer Genome Atlas (TCGA) database, and 239 tissues were collected from RCC patients. RESULTS: TRIM21 silencing attenuated the dependence of RCC cells on fatty acids, and enhanced lipid accumulation in RCC cells. TRIM21 overexpression significantly decreased lipid contents by decreasing the expression of lipogenic enzymes via ubiquitination-mediated degradation of SREBF1. SREBF1 is critical for TRIM21-mediated lipogenesis inhibition in vitro and in vivo. Moreover, TRIM21 expression is negatively correlated with SREBF1 expression, and TRIM21-SREBF1 is a reliable combinational biomarker for RCC prognosis. CONCLUSION: The findings from this study reveal a novel pathway through which TRIM21 inhibits the lipid metabolism process of RCC and shed light on the development of targeted metabolic treatment and prognosis diagnosis of RCC.

The emerging roles of TRIM21 in coordinating cancer metabolism, immunity and cancer treatment.

Tripartite motif containing-21 (TRIM21), an E3 ubiquitin ligase, was initially found to be involved in antiviral responses and autoimmune diseases. Recently studies have reported that TRIM21 plays a dual role in cancer promoting and suppressing in the occurrence and development of various cancers. Despite the fact that TRIM21 has effects on multiple metabolic processes, inflammatory responses and the efficacy of tumor therapy, there has been no systematic review of these topics. Herein, we discuss the emerging role and function of TRIM21 in cancer metabolism, immunity, especially the immune response to inflammation associated with tumorigenesis, and also the cancer treatment, hoping to shine a light on the great potential of targeting TRIM21 as a therapeutic target.

LncRNA LINC00460 facilitates the proliferation and metastasis of renal cell carcinoma via PI3K/AKT signaling pathway.

Renal cell carcinoma (RCC) is one of the most prevalent cancers diseases in the worldwide. Long noncoding RNAs (LncRNAs) have been indicated as a mediator acted in tumorigenesis of RCC. LINC00460 has been reported to participate in many kinds of malignancies and promotes cancer progressions. However, the mechanism of LINC00460 on RCC is yet to be investigated. This study aimed to explore the potential function and regulation mechanism of LINC00460 in RCC. We analysed the LINC00460 expression and the prognosis in RCC patients using Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) databases. LINC00460 level in normal renal cell line and RCC cell lines were examined by qRT-PCR. We study the effects of LINC00460 on proliferation, migration, invasion, apoptosis in RCC cells lines using a series of in vivo and in vitro experiments. RNA sequencing (RNA-seq) analysis was applied to searching potential LINC00460 related signal pathway in RCC. We identified the significant up-regulated expression of LINC00460 both in RCC tissues and cell. RCC patients with elevated LINC00460 expression have shorter survival. Up-expression of LINC00460 promoted cell proliferation, invasion and migration, meanwhile down-regulation of LINC00460 exerted inhibitory effect on these activities. We crucially identified that LNC00460 promotes development of RCC by influencing the PI3K/AKT pathway. Knockdown of LNC00460 decreased the phosphorylation of AKT and mTOR. The key finding of our study showed that LINC00460 functions as an oncogene in RCC pathogenesis by mediating the PI3K/AKT.

DNMT1-mediated epigenetic silencing of TRAF6 promotes prostate cancer tumorigenesis and metastasis by enhancing EZH2 stability.

A plethora of studies have shown that both DNMT1 and EZH2 have great effects on the progression of a variety of cancers. However, it remains unclear whether the expression profiles of these two epigenetic enzymes are molecularly intertwined in prostate cancer (PC), especially in castration-resistant prostate cancer (CRPC). Here, we found that DNMT1 is highly expressed and facilitates PC cell proliferation and migration. Importantly, we demonstrate that the abrogation of DNMT1 expression can induce the decreased expression of EZH2, resulting in the less aggressive capacity of PC cells. Mechanistically, we discovered that DNMT1 promotes PC tumorigenesis and metastasis by inhibiting TRAF6 transcriptional expression and subsequent TRAF6-mediated EZH2 ubiquitination. Finally, we confirmed that there is a negative correlation between DNMT1 and TRAF6 expression and a positive correlation between DNMT1 and EZH2 expression in PC patients. In this study, we first disclose that there is a direct crosstalk between DNA methyltransferase DNMT1 expression and histone methyltransferase EZH2 expression in tumorigenesis and cancer metastasis in vitro and in vivo. Our results also show that targeting DNMT1 with its inhibitor decitabine (an FDA-approved drug) is an appealing treatment strategy for CRPC patients through epigenetic suppression of both DNMT1-mediated DNA methylation and EZH2-modulated histone methylation.

Transketolase promotes colorectal cancer metastasis through regulating AKT phosphorylation.

Transketolase (TKT) which is an important metabolic enzyme in the pentose phosphate pathway (PPP) participates in maintaining ribose 5-phosphate levels. TKT is necessary for maintaining cell growth. However, we found that in addition to this, TKT can also affect tumor progression through other ways. Our previous study indicate that TKT could promote the development of liver cancer by affecting bile acid metabolism. And in this study, we discovered that TKT expression was remarkably upregulated in colorectal cancer, abnormal high expression of TKT is associated with poor prognosis of colorectal cancer. Additionally, TKT promoted colorectal cancer cell growth and metastasis. Further study demonstrated that TKT interacted with GRP78 and promoted colorectal cancer cell glycolysis through increasing AKT phosphorylation, thereby enhancing colorectal cancer cell metastasis. Thus, TKT is expected to become an indicator for judging the prognosis of colorectal cancer, and provide a theoretical basis for drug development of new treatment targets for colorectal cancer.

Expanding uncapped translation and emerging function of circular RNA in carcinomas and noncarcinomas.

Circular RNAs (circRNAs) are classified as noncoding RNAs because they are devoid of a 5' end cap and a 3' end poly (A) tail necessary for cap-dependent translation. However, increasing numbers of translated circRNAs identified through high-throughput RNA sequencing overlapping with polysome profiling indicate that this rule is being broken. CircRNAs can be translated in cap-independent mechanism, including IRES (internal ribosome entry site)-initiated pattern, MIRES (m6A internal ribosome entry site) -initiated patterns, and rolling translation mechanism (RCA). CircRNA-encoded proteins harbour diverse functions similar to or different from host proteins. In addition, they are linked to the modulation of human disease including carcinomas and noncarcinomas. CircRNA-related translatomics and proteomics have attracted increasing attention. This review discusses the progress and exclusive characteristics of circRNA translation and highlights the latest mechanisms and regulation of circRNA translatomics. Furthermore, we summarize the extensive functions and mechanisms of circRNA-derived proteins in human diseases, which contribute to a better understanding of intricate noncanonical circRNA translatomics and proteomics and their therapeutic potential in human diseases.

PRMT1-mediated EZH2 methylation promotes breast cancer cell proliferation and tumorigenesis.

Protein arginine methyltransferase 1 (PRMT1) is able to promote breast cancer cell proliferation. However, the detailed mechanisms of PRMT1-mediated breast cancer cell proliferation are largely unknown. In this study, we reveal that PRMT1-mediated methylation of EZH2 at the R342 site (meR342-EZH2) has a great effect on PRMT1-induced cell proliferation. We also demonstrate that meR342-EZH2 can accelerate breast cancer cell proliferation in vitro and in vivo. Further, we show that meR342-EZH2 promotes cell cycle progression by repressing P16 and P21 transcription expression. In terms of mechanism, we illustrate that meR342-EZH2 facilitates EZH2 binding with SUZ12 and PRC2 assembly by preventing AMPKα1-mediated phosphorylation of pT311-EZH2, which results in suppression of P16 and P21 transcription by enhancing EZH2 expression and H3K27me3 enrichment at P16 and P21 promoters. Finally, we validate that the expression of PRMT1 and meR342-EZH2 is negatively correlated with pT311-EZH2 expression. Our findings suggest that meR342-EZH2 may become a novel therapeutic target for the treatment of breast cancer.

Long noncoding RNA SH3PXD2A-AS1 promotes colorectal cancer progression by regulating p53-mediated gene transcription.

Long non-coding RNAs (lncRNAs) play key roles in various human cancers. We aimed to determine the key lncRNAs mediating colorectal cancer (CRC) progression. We identified some lncRNAs aberrantly expressed in CRC tissues by using lncRNA microarrays and demonstrated that SH3PXD2A-AS1 was one of the most highly overexpressed lncRNAs in CRC. We further aimed to explore the roles and possible molecular mechanisms of SH3PXD2A-AS1 in CRC. RNA ISH revealed that SH3PXD2A-AS1 was overexpressed in CRC compared with adjacent normal colon tissues and indicated poor prognosis in CRC. Functional analyses showed that SH3PXD2A-AS1 enhanced cell proliferation, angiogenesis, and metastasis. Mechanistically, SH3PXD2A-AS1 can directly interact with p53 protein and regulate p53-mediated gene transcription in CRC. We provided mechanistic insights into the regulation of SH3PXD2A-AS1 on p53-mediated gene transcription and suggested its potential as a new prognostic biomarker and target for the clinical management of CRC.

Trim21-mediated HIF-1α degradation attenuates aerobic glycolysis to inhibit renal cancer tumorigenesis and metastasis.

Tripartite motif-containing 21 (Trim21) is mainly involved in antiviral responses and autoimmune diseases. Although Trim21 has been reported to have a cancer-promoting or anticancer effect in various tumours, its role in renal cell cancer (RCC) remains to be elucidated. In this study, we demonstrate that Trim21 is downregulated in primary RCC tissues. Low Trim21 expression in RCC is correlated with poor clinicopathological characteristics and short overall survival. Moreover, we illustrate that Trim21 inhibits RCC cells glycolysis through the ubiquitination-mediated degradation of HIF-1α, which inhibits the proliferation, tumorigenesis, migration, and metastasis of RCC cells in vitro and in vivo. Our findings show that Trim21 may become a promising predictive biomarker for the prognosis of patients with RCC.

Role of Circular RNA in Kidney-Related Diseases.

The kidney is vital in maintaining fluid, electrolyte, and acid-base balance. Kidney-related diseases, which are an increasing public health issue, can happen to people of any age and at any time. Circular RNAs (circRNAs) are endogenous RNA that are produced by selective RNA splicing and are involved in progression of various diseases. Studies have shown that various kidney diseases, including renal cell carcinoma, acute kidney injury, and chronic kidney disease, are linked to circRNAs. This review outlines the characteristics and biological functions of circRNAs and discusses specific studies that provide insights into the function and potential of circRNAs for application in the diagnosis and treatment of kidney-related diseases.

LINC00460/DHX9/IGF2BP2 complex promotes colorectal cancer proliferation and metastasis by mediating HMGA1 mRNA stability depending on m6A modification.

BACKGROUND: Increasing studies have shown that long noncoding RNAs (lncRNAs) are pivotal regulators participating in carcinogenic progression and tumor metastasis in colorectal cancer (CRC). Although lncRNA long intergenic noncoding RNA 460 (LINC00460) has been reported in CRC, the role and molecular mechanism of LINC00460 in CRC progression still requires exploration. METHODS: The expression levels of LINC00460 were analyzed by using a tissue microarray containing 498 CRC tissues and their corresponding non-tumor adjacent tissues. The correlations between the LINC00460 expression level and clinicopathological features were evaluated. The functional characterization of the role and molecular mechanism of LINC00460 in CRC was investigated through a series of in vitro and in vivo experiments. RESULTS: LINC00460 expression was increased in human CRC, and high LINC00460 expression was correlated with poor five-year overall survival and disease-free survival. LINC00460 overexpression sufficiently induced the epithelial-mesenchymal transition and promoted tumor cell proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. In addition, LINC00460 enhanced the protein expression of high-mobility group AT-hook 1 (HMGA1) by directly interacting with IGF2BP2 and DHX9 to bind the 3' untranslated region (UTR) of HMGA1 mRNA and increased the stability of HMGA1 mRNA. In addition, the N6-methyladenosine (m6A) modification of HMGA1 mRNA by METTL3 enhanced HMGA1 expression in CRC. Finally, it suggested that HMGA1 was essential for LINC00460-induced cell proliferation, migration, and invasion. CONCLUSIONS: LINC00460 may be a novel oncogene of CRC through interacting with IGF2BP2 and DHX9 and bind to the m6A modified HMGA1 mRNA to enhance the HMGA1 mRNA stability. LINC00460 can serve as a promising predictive biomarker for the diagnosis and prognosis among patients with CRC.

Global and Site-Specific Effect of Phosphorylation on Protein Turnover.

To date, the effects of specific modification types and sites on protein lifetime have not been systematically illustrated. Here, we describe a proteomic method, DeltaSILAC, to quantitatively assess the impact of site-specific phosphorylation on the turnover of thousands of proteins in live cells. Based on the accurate and reproducible mass spectrometry-based method, a pulse labeling approach using stable isotope-labeled amino acids in cells (pSILAC), phosphoproteomics, and a unique peptide-level matching strategy, our DeltaSILAC profiling revealed a global, unexpected delaying effect of many phosphosites on protein turnover. We further found that phosphorylated sites accelerating protein turnover are functionally selected for cell fitness, enriched in Cyclin-dependent kinase substrates, and evolutionarily conserved, whereas the glutamic acids surrounding phosphosites significantly delay protein turnover. Our method represents a generalizable approach and provides a rich resource for prioritizing the effects of phosphorylation sites on protein lifetime in the context of cell signaling and disease biology.