Metabolic reprogramming directed by super-enhancers in tumors: An emerging landscape.

Metabolic reprogramming is an essential hallmark of tumors, and metabolic abnormalities are strongly associated with the malignant phenotype of tumor cells. This is closely related to transcriptional dysregulation. Super-enhancers are extremely active cis-regulatory regions in the genome, and can amalgamate a complex set of transcriptional regulatory components that are crucial for establishing tumor cell identity, promoting tumorigenesis, and enhancing aggressiveness. In addition, alterations in metabolic signaling pathways are often accompanied by changes in super-enhancers. Presently, there is a surge in interest in the potential pathogenesis of various tumors through the transcriptional regulation of super-enhancers and oncogenic mutations in super-enhancers. In this review, we summarize the functions of super-enhancers, oncogenic signaling pathways, and tumor metabolic reprogramming. In particular, we focus on the role of the super-enhancer in tumor metabolism and its impact on metabolic reprogramming. This review also discusses the prospects and directions in the field of super-enhancer and metabolic reprogramming.

Anchoring super-enhancer-driven oncogenic lncRNAs for anti-tumor therapy in hepatocellular carcinoma.

Super-enhancer (SE) plays a vital role in the determination of cell identity and fate. Up-regulated expression of coding genes is frequently associated with SE. However, the transcription dysregulation driven by SE, from the viewpoint of long non-coding RNA (lncRNA), remains unclear. Here, SE-associated lncRNAs in HCC are comprehensively outlined for the first time. This study integrally screens and identifies several novel SE-associated lncRNAs that are highly abundant and sensitive to JQ1. Especially, HSAL3 is identified as an uncharacterized SE-driven oncogenic lncRNA, which is activated by transcription factors HCFC1 and HSF1 via its super-enhancer. HSAL3 interference negatively regulates NOTCH signaling, implying the potential mechanism of its tumor-promoting role. The expression of HSAL3 is increased in HCC samples, and higher HSAL3 expression indicates an inferior overall survival of HCC patients. Furthermore, siHSAL3 loaded nanoparticles exert anti-tumor effect on HCC in vitro and in vivo. In conclusion, this is the first comprehensive survey of SE-associated lncRNAs in HCC. HSAL3 is a novel SE-driven oncogenic lncRNA, and siHSAL3 loaded nanoparticles are therapeutic candidates for HCC. This work sheds lights on the merit of anchoring SE-driven oncogenic lncRNAs for HCC treatment.

Diagnostic value of nerve conduction study in NOTCH2NLC-related neuronal intranuclear inclusion disease.

BACKGROUND AND AIMS: Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disorder mainly caused by abnormally expanded GGC repeats within the NOTCH2NLC gene. Most patients with NIID show polyneuropathy. Here, we aim to investigate diagnostic electrophysiological markers of NIID. METHODS: In this retrospective dual-center study, we reviewed 96 patients with NOTCH2NLC-related NIID, 94 patients with genetically confirmed Charcot-Marie-Tooth (CMT) disease, and 62 control participants without history of peripheral neuropathy, who underwent nerve conduction studies between 2018 and 2022. RESULTS: Peripheral nerve symptoms were presented by 53.1% of patients with NIID, whereas 97.9% of them showed peripheral neuropathy according to electrophysiological examinations. Patients with NIID were characterized by slight demyelinating sensorimotor polyneuropathy; some patients also showed mild axonal lesions. Motor nerve conduction velocity (MCV) of the median nerve usually exceeded 35 m/s, and were found to be negatively correlated with the GGC repeat sizes. Regarding the electrophysiological differences between muscle weakness type (n = 27) and non-muscle weakness type (n = 69) of NIID, nerve conduction abnormalities were more severe in the muscle weakness type involving both demyelination and axonal impairment. Notably, specific DWI subcortical lace sign was presented in only 33.3% of muscle weakness type, thus it was difficult to differentiate them from CMT. Combining age of onset, distal motor latency, and compound muscle action potential of the median nerve showed the optimal diagnostic performance to distinguish NIID from major CMT (AUC = 0.989, sensitivity = 92.6%, specificity = 97.4%). INTERPRETATION: Peripheral polyneuropathy is common in NIID. Our study suggest that nerve conduction study is useful to discriminate NIID.

Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders.

Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.

Clinical features of NOTCH2NLC-related neuronal intranuclear inclusion disease.

BACKGROUND: Abnormal expanded GGC repeats within the NOTCH2HLC gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of NOTCH2NLC-related NIID in China. METHODS: Patients with NOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy. RESULTS: In the 247 patients with NOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=-0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission. CONCLUSIONS: NIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of NOTCH2NLC-related NIID.

Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases.

NADH:ubiquinone oxidoreductase core subunit S8 (NDUFS8) is an essential core subunit and component of the iron-sulfur (FeS) fragment of mitochondrial complex I directly involved in the electron transfer process and energy metabolism. Pathogenic variants of the NDUFS8 are relevant to infantile-onset and severe diseases, including Leigh syndrome, cancer, and diabetes mellitus. With over 1000 nuclear genes potentially causing a mitochondrial disorder, the current diagnostic approach requires targeted molecular analysis, guided by a combination of clinical and biochemical features. Currently, there are only several studies on pathogenic variants of the NDUFS8 in Leigh syndrome, and a lack of literature on its precise mechanism in cancer and diabetes mellitus exists. Therefore, NDUFS8-related diseases should be extensively explored and precisely diagnosed at the molecular level with the application of next-generation sequencing technologies. A more distinct comprehension will be needed to shed light on NDUFS8 and its related diseases for further research. In this review, a comprehensive summary of the current knowledge about NDUFS8 structural function, its pathogenic mutations in Leigh syndrome, as well as its underlying roles in cancer and diabetes mellitus is provided, offering potential pathogenesis, progress, and therapeutic target of different diseases. We also put forward some problems and solutions for the following investigations.

Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor.

Essential tremor is one of the most common movement disorders. Despite its high prevalence and heritability, the genetic aetiology of essential tremor remains elusive. Up to now, only a few genes/loci have been identified, but these genes have not been replicated in other essential tremor families or cohorts. Here we report a genetic study in a cohort of 197 Chinese pedigrees clinically diagnosed with essential tremor. Using a comprehensive strategy combining linkage analysis, whole-exome sequencing, long-read whole-genome sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal GGC repeat expansion in the 5' region of the NOTCH2NLC gene that co-segregated with disease in 11 essential tremor families (5.58%) from our cohort. Clinically, probands that had an abnormal GGC repeat expansion were found to have more severe tremor phenotypes, lower activities of daily living ability. Obvious genetic anticipation was also detected in these 11 essential tremor-positive families. These results indicate that abnormal GGC repeat expansion in the 5' region of NOTCH2NLC gene is associated with essential tremor, and provide strong evidence that essential tremor is a family of diseases with high clinical and genetic heterogeneities.

Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations.

BACKGROUND: The genetic causes for most male infertility due to severe asthenozoospermia remain unclear. OBJECTIVE: Our objective was to identify unknown genetic factors in 47 patients with severe asthenozoospermia from 45 unrelated Chinese families. METHODS: We performed whole exome sequencing of 47 individuals with severe asthenozoospermia from 45 unrelated families. Mutation screening was performed in a control cohort of 637 individuals, including 219 with oligoasthenospermia, 195 with non-obstructive azoospermia and 223 fertile controls. Ultrastructural and immunostaining analyses of patients' spermatozoa were performed to characterise the effect of variants. RESULTS: One homozygous non-sense mutation (NM_194302, c.G5341T:p.E1781X), two compound heterozygous mutations (c.C2284T:p.R762X and c.1751delC:p.P584fs) and two compound heterozygous mutations (c.5714_5721del:p.L1905fs and c.C3021A:p.N1007K) were identified in CFAP65 of three individuals with completely immotile spermatozoa, respectively. No biallelic deleterious variants of CFAP65 were detected in the control cohort of 637 individuals. Ultrastructural and immunostaining analyses of spermatozoa from two patients showed highly aberrant sperm morphology with severe defects such as acrosome hypoplasia, disruption of the mitochondrial sheath and absence of the central pair complex. CONCLUSION: To the best of our knowledge, we are the first to report that CFAP65 mutations may cause spermatozoa to be completely immotile.

The role of miR-205 in the VEGF-mediated promotion of human ovarian cancer cell invasion.

OBJECTIVE: Our objective was to investigate a miRNA pathway that acts downstream of VEGF-induced invasion of ovarian cancer cells. METHOD: We used two paired high and low metastatic serous ovarian cancer cells to demonstrate the role of miR-205 in VEGF-induced invasion of ovarian cancer cells and to investigate the gene targets of miR-205. RESULTS: Our previous comparative proteomics studies showed that VEGF decreased the expression of Ezrin and Lamin A/C, and this result was validated in the present study using qPCR and Western blotting. Then we found that VEGF enhanced the invasiveness of and inhibited apoptosis in ovarian cancer cells as assessed by transwell invasion assays and Annexin V-FITC immunostaining, respectively. VEGFR was also expressed in ovarian cancer cells, as assessed by immunocytochemical staining. Furthermore, using the dual-luciferase report assay system, we demonstrated that miR-205 targeted Ezrin and Lamin A/C. MiR-205 was up-regulated in ovarian cancer cells exposed to VEGF, as determined by miRNA microarray analysis and verified by qPCR. MiR-205 promoted the invasion and proliferation of ovarian cancer cells. CONCLUSION: Our data reveal a new potential pathway in which VEGF promotes the invasion of ovarian cancer cells, partially via the down-regulation of Ezrin and Lamin A/C caused by increased expression of miR-205.

Reheating constraints to inflationary models.

Evidence from the BICEP2 experiment for a significant gravitational-wave background has focused attention on inflaton potentials V(ϕ)∝ϕ(α) with α = 2 ("chaotic" or "m(2)ϕ(2)" inflation) or with smaller values of α, as may arise in axion-monodromy models. Here we show that reheating considerations may provide additional constraints to these models. The reheating phase preceding the radiation era is modeled by an effective equation-of-state parameter w(re). The canonical reheating scenario is then described by w(re) = 0. The simplest α = 2 models are consistent with w(re) = 0 for values of n(s) well within the current 1σ range. Models with α = 1 or α = 2/3 require a more exotic reheating phase, with -1/3 < w(re) < 0, unless n(s) falls above the current 1σ range. Likewise, models with α = 4 require a physically implausible w(re) > 1/3, unless n(s) is close to the lower limit of the 2σ range. For m(2)ϕ(2) inflation and canonical reheating as a benchmark, we derive a relation log(10)(T(re)/10(6) GeV) ≃ 2000(n(s)-0.96) between the reheat temperature T(re) and the scalar spectral index n(s). Thus, if n(s) is close to its central value, then T(re) ≲ 10(6) GeV, just above the electroweak scale. If the reheat temperature is higher, as many theorists may prefer, then the scalar spectral index should be closer to n(s) ≃ 0.965 (at the pivot scale k = 0.05 Mpc(-1)), near the upper limit of the 1σ error range. Improved precision in the measurement of n(s) should allow m(2)ϕ(2), axion monodromy, and ϕ(40) models to be distinguished, even without precise measurement of r, and to test the m(2)ϕ(2) expectation of n(s) ≃ 0.965.

Mitochondria-related chemoradiotherapy resistance genes-based machine learning model associated with immune cell infiltration on the prognosis of esophageal cancer and its value in pan-cancer.

Esophageal cancer, known for its high incidence and low five-year survival rate, poses significant treatment challenges. A key aspect of this challenge is the close link between mitochondria and resistance to chemoradiotherapy (CRT). Currently, there is a scarcity of biomarkers for predicting CRT response and prognosis in esophageal cancer. Our study addresses this gap by developing a prognostic model that incorporates mitochondria-related CRT resistance (MRCRTR) genes, including CTSL, TBL1X, CLN8, MMP1, PDPN, and MRPL37. Survival analysis using Kaplan-Meier curves reveals that patients with high MRCRTR scores have lower survival rates than those with low scores. Utilizing a nomogram, we successfully predict the one-, two-, and three-year overall survival rates for esophageal cancer patients. Cox regression analysis confirms the MRCRTR score as an independent prognostic factor. Furthermore, our single-cell and correlation analyses suggested that MRCRTR genes might influence CRT resistance by modulating the immune microenvironment and impacting angiogenesis. Our pan-cancer analysis also indicates the potential applicability of MRCRTR scores to head and neck squamous cell carcinoma. The validation of these findings, conducted with samples from Xiang-ya Hospital, aligns closely with our bioinformatics results. Our study not only explores the role of MRCRTR genes in predicting the prognosis of esophageal cancer but also enhances the understanding of the interplay between CRT, mitochondria, and patient outcomes.

Downregulation of Beclin 1 and impairment of autophagy in a small population of colorectal cancer.

BACKGROUND: Autophagy is a highly conserved mechanism for degradation and recycling of long-lived proteins and damaged organelle to maintain cell homeostasis. Deregulation of autophagy has been associated with tumorigenesis. Beclin 1 is an essential autophagy protein and its upregulation has been observed in most colorectal cancer tissues. However, there is a small population of colorectal cancers with downregulation of Beclin 1. AIM: The purpose of this study was to investigate the role autophagy plays in colorectal cancers with downregulation of Beclin 1. METHODS: LC3 protein, an autophagosome marker, was assessed by ICH and WB in colorectal cancers tissues. An anti-tumor effect of Beclin 1 was examined by introducing exogenous Beclin 1 in vitro. Colony formation assay, growth curves and mouse xenograft were analysed. RESULTS: Our results showed that LC3 was suppressed in the colorectal cancers (9.86 %) with downregulation of Beclin 1. Moreover, overexpression of Beclin 1 inhibited colorectal cancer cell growth and enhanced the rapamycin-induced antitumor effect in vitro. CONCLUSION: Downregulation of Beclin 1 and autophagy inhibition play an important role in a part of colorectal cancers. Activating autophagy or overexpression of Beclin 1 may be an effective treatment for some colorectal cancers. Detection of expression profile of Beclin 1 in colorectal cancers could be a strategy for new diagnostic and therapeutic methods.

Proteomics-based analysis of differentially expressed proteins in the CXCR1-knockdown gastric carcinoma MKN45 cell line and its parental cell.

C-X-C chemokine receptor types 1 (CXCR1), a cell-surface G-protein-coupled receptor has been found to be associated with tumorigenesis, development, and progression of some tumors. Previously, we have found that CXCR1 overexpression is associated with late-stage gastric adenocarcinoma. We also have demonstrated that knockdown of CXCR1 could inhibit cell proliferation in vitro and in vivo. In this study, we compared the changes of protein expression profile between gastric carcinoma MKN45 cell line and CXCR1-knockdown MKN45 cell line by 2D electrophoresis. Among the 101 quantified proteins, 29 spots were significantly different, among which 13 were down-regulated and 16 were up-regulated after CXCR1 knockdown. These proteins were further identified by mass spectrometry analysis. Among them, several up-regulated proteins such as hCG2020155, Keratin8, heterogeneous nuclear ribonucleoprotein C (C1/C2), and several down-regulated proteins such as Sorcin, heat shock protein 27, serpin B6 isoform b, and heterogeneous nuclear ribonucleoprotein K were confirmed. These proteins are related to cell cycle, the transcription regulation, cell adherence, cellular metabolism, drug resistance, and so on. These results provide an additional support to the hypothesis that CXCR1 might play an important role in proliferation, invasion, metastasis, and prognosis, and drug resistance of gastric carcinoma.

Mechanisms of impairment in hair and scalp induced by hair dyeing and perming and potential interventions.

With the rapid growth of beauty and personal care industries, many hair-relevant products, hair dyes and hair perms in particular, are increasingly prevalent in both women and men, regardless of being young or old as they frequently change hair color or shape to enhance youthfulness and beauty and to follow fashion trends. Hair dyes and perms alter hair color and/or shape by mechanically changing the physical structure and chemical substances of the hair shaft. However, treatment of hair with chemical formulations has been potentially ascribed to adverse outcomes in the hair shaft including structure damage, chemical constituent disorder, and impaired physical properties, although hair cosmetics procedures are intrinsically safe. Nevertheless, the mechanisms of impairment in the hair shaft and scalp induced by hair dyeing and perming remain elusive. Additionally, adverse reactions activated by exposure to specific chemical ingredients including skin irritation, allergic contact dermatitis (ACD), and even cancer risk have been reported clinically, but existing evidence is not consistent enough in the case of human studies. Herein, the review aims to give an overview of hair cosmetics, especially concerning the basic knowledge about various hair dyes and perms, the consequences for hair shafts and the scalp resulting from the application of hair cosmetics mentioned above, mechanisms of hazardous outcomes, and potential desirable interventions to alleviate the impairment.

Multiscale Analysis of the Highly Stretchable Carbon-Based Polymer Strain Sensor.

In this paper, a multiscale analysis method was proposed to simulate carbon nanoparticles (CNPs)-filled polymers which can be strain sensors applied in wearable electronic devices, flexible skin, and health monitoring fields. On the basis of the microstructure characteristics of the composite, a microscale representative volume element model of the CNPs-filled polymer was established using the improved nearest-neighbor algorithm. By finite element analysis, the variation of the junction widths of adjacent aggregates can be extracted from the simulation results. Then, according to the conductive mechanism of CNP-filled polymers, the composite was simplified as a circuit network composed of vast random resistors which were determined by the junction widths between adjacent aggregates. Hence, by taking junction widths as the link, the resistance variation of the CNPs-filled polymer with the strain can be obtained. To verify the proposed method, the electromechanical responses of silicone elastomer filled with different CNPs under different filling amounts were investigated numerically and experimentally, respectively, and the results were in good agreement. Therefore, the multiscale analysis method can not only reveal the strain-sensing mechanism of the composite from the microscale, but also effectively predict the electromechanical behavior of the CNPs-filled polymer with different material parameters.

Crosstalk between N6-methyladenosine (m6A) modification and noncoding RNA in tumor microenvironment.

N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotes, and it participates in the regulation of pathophysiological processes in various diseases, including malignant tumors, by regulating the expression and function of both coding and non-coding RNAs (ncRNAs). More and more studies demonstrated that m6A modification regulates the production, stability, and degradation of ncRNAs and that ncRNAs also regulate the expression of m6A-related proteins. Tumor microenvironment (TME) refers to the internal and external environment of tumor cells, which is composed of numerous tumor stromal cells, immune cells, immune factors, and inflammatory factors that are closely related to tumors occurrence and development. Recent studies have suggested that crosstalk between m6A modifications and ncRNAs plays an important role in the biological regulation of TME. In this review, we summarized and analyzed the effects of m6A modification-associated ncRNAs on TME from various perspectives, including tumor proliferation, angiogenesis, invasion and metastasis, and immune escape. Herein, we showed that m6A-related ncRNAs can not only be expected to become detection markers of tumor tissue samples, but can also be wrapped into exosomes and secreted into body fluids, thus exhibiting potential as markers for liquid biopsy. This review provides a deeper understanding of the relationship between m6A-related ncRNAs and TME, which is of great significance to the development of a new strategy for precise tumor therapy.

Emerging role of exosome-derived non-coding RNAs in tumor-associated angiogenesis of tumor microenvironment.

The tumor microenvironment (TME) is an intricate ecosystem that is actively involved in various stages of cancer occurrence and development. Some characteristics of tumor biological behavior, such as proliferation, migration, invasion, inhibition of apoptosis, immune escape, angiogenesis, and metabolic reprogramming, are affected by TME. Studies have shown that non-coding RNAs, especially long-chain non-coding RNAs and microRNAs in cancer-derived exosomes, facilitate intercellular communication as a mechanism for regulating angiogenesis. They stimulate tumor growth, as well as angiogenesis, metastasis, and reprogramming of the TME. Exploring the relationship between exogenous non-coding RNAs and tumor-associated endothelial cells, as well as their role in angiogenesis, clinicians will gain new insights into treatment as a result.

Emerging role of ferroptosis-related circular RNA in tumor metastasis.

Tumor metastasis is an important factor that contributes to the poor prognosis of patients with tumors. Therefore, to solve this problem, research on the mechanism of metastasis is essential. Ferroptosis, a new mode of cell death, is characterized by membrane damage due to lipid peroxidation caused by iron overload. Many studies have shown that excessive ferroptosis can affect tumor metastasis and thus inhibit tumor progression. Recently, circular RNA (circRNA), a type of non-coding RNA, has been shown to be associated with the progression of ferroptosis, thus influencing tumor development. However, the specific mechanisms by which circRNAs affect the progression of ferroptosis and their roles in tumor metastasis are not known. In this review, we systematically discuss the role of circRNAs in regulating tumor ferroptosis and their mechanism of action through sponging miRNAS in various tumors, thereby impacting metastasis. This review helps elucidate the relationship and role of ferroptosis-related circRNAs in tumor metastasis and may provide future researchers with new ideas and directions for targeted therapies.

[Corrigendum] CXCR1 promotes malignant behavior of gastric cancer cells in vitro and in vivo in AKT and ERK1/2 phosphorylation.

Subsequently to the publication of the above article, the authors contacted the Editorial Office to explain that they had inadvertently included data from the same original source in the first row of data panels in Fig. 4B on p. 2191 (showing the results of cell migration assay experiments) to represent two differently performed experiments. Specifically, these images (second and third data panels) containing partially overlapping data corresponded to the 'Vacant­BGC823' in the empty plasmid transfection group and the background 'BGC823 cell' groups, respectively. However, the authors had retained their original data, which they presented to the office for our inspection, and were able to reassemble the data correctly in the figure. The revised version of Fig. 4, showing the replacement data for the 'Vacant­BGC823' and 'BGC823' Migration panels in Fig. 4B, is shown on the next page. The authors are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum, and all the authors agree with its publication. Furthermore, the authors apologize to the readership for any inconvenience caused. [International Journal of Oncology 48: 2184­2196, 2016; DOI: 10.3892/ijo.2016.3428].

Prognostic value of sirtuin family members and experimental verification identify SIRT5 as diagnostic biomarkers in clear cell renal cell carcinoma.

Background: The sirtuins (SIRTs) family is a nicotinamide adenine dinucleotide (NAD+) family of dependent deacetylases, which includes SIRT1-7. This family is related to the development and progression of various tumors. However, a comprehensive analysis of the role of SIRTs in clear cell renal cell carcinoma (ccRCC) is still lacking, and there are few reports on the inhibitory role of SIRT5 in ccRCC. Methods: We used immunohistochemical analysis, and several bioinformatic databases to perform an integrated analysis of the expression and prognostic value of SIRT5 and other SIRT family members in ccRCC along with the associated immune cell infiltration. These databases include TIMER, THPA, cell culture, UALCAN, cBioPortal, WebGestalt, Metascape, DiseaseMeth, STRING database, and Cytoscape. Results: The protein expression of SIRT1, 2, 3, 6, and 7 were upregulated in ccRCC for the Human Protein Atlas database, whereas the expression of SIRT4 and SIRT5 was decreased. The expression based on tumor stage, and grade followed a similar trend. Kaplan-Meier analysis showed that high SIRT4 and SIRT5 expression was positively related to better overall survival (OS), whereas SIRT6 and SIRT7 expression was positively related to worse OS. Further, high SIRT3 expression was related to worse relapse-free survival (RFS), whereas high SIRT5 expression was related to better RFS. To explore the mechanism underlying the function of SIRTs in ccRCC, we also used several databases to perform the functional enrichment analysis and explore the relationship between infiltrating immune cells and seven SIRT family members in ccRCC. The results showed that several SIRT family members, and particularly SIRT5, are correlated with the infiltration of some important immune cells. The protein expression of SIRT5 was significantly lower in tumor tissue compared to normal tissue and was negatively related to the age of the patient ccRCC individual tumor stages, and grades. In human ccRCC samples, strong IHC staining expression of SIRT5 was displayed in adjacent normal tissue than in tumor tissues. Conclusion: SIRT5 may be a prognostic marker and a novel strategy for the treatment of ccRCC.