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Aim: We aimed to identify that long noncoding RNAs (lncRNAs) are involved in ischemia-reperfusion (IR)-induced late fibrosis of kidney and may constitute novel therapeutic strategies for acute kidney injury-induced chronic kidney disease. Materials & methods: We performed the mouse model of IR later induced renal fibrosis and analyzed lncRNA profiles using second-generation sequencing during the pathogenesis. Results: The expression levels of 43 lncRNAs and 141 lncRNAs were respectively changed significantly 7 days and 2 weeks after IR treatment. Based on the correlation analysis of the differentially expressed genes, the interaction networks of lncRNAs, miRNAs and mRNA were structured. Conclusion: LncRNA (Gm12840) could act as a sponge for miR-677-5p to mediate fibroblast activation induced by TGF-β1 via the WISP1/PKB (Akt) signaling pathway.

It has been reported that BCL2L10 is abundantly and specifically expressed in adult human and mouse oocytes and played a very important role in oocytes maturation and early embryonic development. This study is to investigate the expression pattern of BCL2L10 in buffalo ovaries and its effect on the in vitro maturation of buffalo oocytes, so as to dissect mechanism of oocytes maturation and provide theoretical guidance for improvement of the in vitro maturation of buffalo oocytes. The results showed that BCL2L10 gene was enriched in ovary and the expression of BCL2L10 was oocyte specific and up-regulated during oocyte maturation. BCL2L10 protein and mRNA were detectable in buffalo early embryos, upregulated at 2-cell to 8-cell stages and down-regulated in the later stages. Knockdown of BCL2L10 by RNA interference resulted in a significant decrease in the maturation rate (33.5%) and cleavage rate (37.52%) of buffalo oocytes coupled with up-regulation of apoptosis-related gene Caspase-9. We concluded that BCL2L10 is a candidate associated with buffalo oocyte maturation.

Programmed cell death-1 (PD-1) belongs to an inhibitory signaling pathway capable of maintaining central and peripheral immune tolerance. Blockage of PD-1 has been identified as a promising immunotherapeutic approach for cancer and chronic infectious diseases. However, it is unknown whether PD-1 pathway regulates stem cell function. It is generally believed that mesenchymal stem cells (MSCs) produce PD-1 ligand, but fail to express PD-1. In this study, we show that neural crest-derived MSCs from dental pulp (MSC-DP), but not MSCs from bone marrow, expressed PD-1. Knocking down PD-1 expression in MSC-DP results in a significantly reduced capacity for cell proliferation and accelerated multipotential differentiation. Mechanistically, we show that PD-1 regulates a SHP2/ERK/Notch cascade to maintain proliferation and a SHP2/ERK/β-catenin cascade to inhibit osteo-/odontogenic differentiation. This study indicates that PD-1 is a key surface molecule controlling cell proliferation and multipotential differentiation of MSC-DP. Through regulating PD-1/SHP2/ERK signaling, we can significantly improve the quality and quantity of culture-expanded MSC-DP for potential clinical therapies.

This study aimed to disclose differentially expressed genes (DEGs) in dorsal root ganglia (DRGs) of neuropathic pain (NP) from spared nerve injury (SNI) model, thereby identifying specific and meaningful genetic targets for the diagnosis and treatment of NP. The GSE89224 was downloaded from the GEO database. DEGs were screened using the GEO2R online tool. Functional enrichment analysis of DEGs was then performed using the DAVID and constructed using the R ggplot2 package. Protein-protein interaction (PPI) network was constructed from the STRING database and visualized in Cytoscape software. MicroRNA targeting these DEGs was obtained from the TarBase and miRTarBase database, while transcription factor (TF)-targeting DEGs were predicted from the ENCODE database, both of which utilized the visual analytics platform NetworkAnayst. Finally, a merged microRNA-TF network was constructed based on the above two networks and was then analyzed with Cytoscape. Eighty DEGs were screened, only Vstm2b and Htr3a were downregulated and 78 genes were upregulated. The real-time polymerase chain reaction was applied to validate the gene expression of the top five DEGs (Npy, Atf3, Gpr151, Sprr1a, and Cckbr) in the DRG tissue 5 days after SNI surgery. It was found that Npy, Atf3, and Sprr1a have a significant increase after SNI stimulation, while Gpr151 and Cckbr showed a slight upward trend. Functional analysis was performed on all DEGs, of which 58 biological processes were enriched by gene ontology analysis, and 11 signaling pathways were enriched by KEGG analysis. In the PPI network, Atf3, Jun, Timp, and Npy had a higher degree. Thus, combined with various bioinformatic analyses, Npy and Atf3 may serve as the prognostic and therapeutic targets of NP. Key microRNA (mmu-mir-16-5p) and TF (MEF2A) were predicted to be associated with the pathogenetic process of NP with microRNA-TF regulatory network analysis, which were also identified as key regulators in the progression of NP.

Mineralocorticoid receptor (MR) has been considered as a potential target for treating atherosclerosis. However, the cellular and molecular mechanisms are not completely understood. We aim to explore the functions and mechanisms of macrophage MR in atherosclerosis. Atherosclerosis-susceptible LDLRKO chimeric mice with bone marrow cells from floxed control mice or from myeloid MR knock-out (MRKO) mice were generated and fed with high cholesterol diet. Oil red O staining showed that MRKO decreased atherosclerotic lesion area in LDLRKO mice. In another mouse model of atherosclerosis, MRKO/APOEKO mice and floxed control/APOEKO mice were generated and treated with angiotensin II. Similarly, MRKO inhibited the atherosclerotic lesion area in APOEKO mice. Histological analysis showed that MRKO increased collagen coverage and decreased necrosis and macrophage accumulation in the lesions. In vitro results demonstrated that MRKO suppressed macrophage foam cell formation and up-regulated the expression of genes involved in cholesterol efflux. Furthermore, MRKO decreased accumulation of apoptotic cells and increased effective efferocytosis in atherosclerotic lesions. In vitro study further revealed that MRKO increased the phagocytic index of macrophages without affecting their apoptosis. In conclusion, MRKO reduces high cholesterol- or angiotensin II-induced atherosclerosis and favorably changes plaque composition, likely improving plaque stability. Mechanistically, MR deficiency suppresses macrophage foam cell formation and up-regulates expression of genes related to cholesterol efflux, as well as increases effective efferocytosis and phagocytic capacity of macrophages.

The testicular seminiferous tubules contain Sertoli cells and different types of spermatogenic cells. They provide the microenvironment for spermatogenesis, but the precise molecular mechanism of spermatogenesis is still not well known. Here, we have employed tandem mass tag coupled to LC-MS/MS with the high-throughput quantitative proteomics technology to explore the protein expression from buffalo testicular seminiferous tubules at three different developmental stages (prepuberty, puberty, and postpuberty). The results show 304 differentially expressed proteins with a ≥2-fold change, and bioinformatics analysis indicates that 27 of these may be associated with spermatogenesis. Expression patterns of seven selected proteins were verified via Western blot and quantitative RT-PCR analysis, and further cellular localizations of these proteins by immunohistochemical or immunofluorescence analysis. Taken together, the results provide potential molecular markers of spermatogenesis and provide a rich resource for further studies on male reproduction regulation.

Fibrosis is the final common pathological feature of a wide variety of chronic kidney disease (CKD). However, an understanding of the mechanisms underlying the development of renal fibrosis remains challenging and controversial. As the current focus of molecular research, noncoding RNAs (ncRNAs), mainly microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular noncoding RNAs (circRNAs), have powerful and abundant biological functions, which essentially makes them mediators of the physiological and pathological processes of various system diseases. The role of ncRNAs in renal fibrosis has also received great attention in recent years, but most research has mainly focused on miRNAs. In fact, although a large number of studies of lncRNAs have emerged recently, the role these molecules play in renal fibrosis haven't been fully understood till now. Thus, this review discusses the discovery of lncRNAs and their biological functions in different types of renal fibrosis, as well as the imminent applications of these findings in clinical use. Undoubtedly, in the future, further understanding of the function of all types of lncRNAs will reveal large breakthroughs in the treatment of renal fibrosis.

Disrupted Wnt signaling in osteoblastic-lineage cells leads to bone formation defect in osteoporosis. However, the factors repressing Wnt signaling are unclear. In our study, we found that Wnt signaling was suppressed persistently in bone marrow-derived mesenchymal stem cells (BMSCs) during osteoporosis. Accordingly, histone acetylation levels on Wnt genes (Wnt1, Wnt6, Wnt10a, and Wnt10b) were declined in BMSCs from OVX mice. By screening the family of histone acetyltransferase, we identified that GCN5 expression increased during osteogenic differentiation of BMSCs, whereas decreased after osteoporosis. Further analysis revealed that GCN5 promoted osteogenic differentiation of BMSCs by increasing acetylation on histone 3 lysine 9 loci on the promoters of Wnt genes. Reduced GCN5 expression suppressed Wnt signaling, resulting in osteogenic defect of BMSCs from OVX mice. Moreover, restoring GCN5 levels recovered BMSC osteogenic differentiation, and attenuated bone loss in OVX mice. Taken together, our study demonstrated that disrupted histone acetylation modification in BMSCs lead to bone formation defect during osteoporosis. The findings also introduced a novel therapeutic target for osteoporosis.

Summary Aging drives the accumulation of senescent cells (SnCs) including stem/progenitor cells in bone marrow, which contributes to aging‐related bone degenerative pathologies. Local elimination of SnCs has been shown as potential treatment for degenerative diseases. As LepR+ mesenchymal stem/progenitor cells (MSPCs) in bone marrow are the major population for forming bone/cartilage and maintaining HSCs niche, whether local elimination of senescent LepR+ MSPCs delays aging‐related pathologies and improves local microenvironment need to be well defined. In this study, we performed local delivery of tetramethylpyrazine (TMP) in bone marrow of aging mice, which previously showed to be used for the prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP). We found the increased accumulation of senescent LepR+ MSPCs in bone marrow of aging mice, and TMP significantly inhibited the cell senescent phenotype via modulating Ezh2‐H3k27me3. Most importantly, local delivery of TMP improved bone marrow microenvironment and maintained bone homeostasis in aging mice by increasing metabolic and anti‐inflammatory responses, inducing H‐type vessel formation, and maintaining HSCs niche. These findings provide evidence on the mechanisms, characteristics and functions of local elimination of SnCs in bone marrow, as well as the use of TMP as a potential treatment to ameliorate human age‐related skeletal diseases and to promote healthy lifespan.

Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro passaging leads to stemness loss of MSCs, resulting in failure of MSCs therapy. Here, we report a melatonin-based strategy to improve cell therapy of in vitro cultured MSCs. Among four small molecules with anti-aging and stem cell-protection properties (rapamycin, resveratrol, quercetin and melatonin), colony forming, proliferation, and osteogenic differentiation assay showed that melatonin was the most efficient to preserve self-renewal and differentiation properties of rat bone marrow MSCs (BMMSCs) after long-term passaging. Functional assays confirmed melatonin treatment did not affect the colony forming, proliferation and osteogenic differentiation of BMMSCs cultured for 1 or 4 passages, but largely prevented the decline of self-renew and differentiation capacity of BMMSCs cultured for 15 passages in vitro. Furthermore, heterotopic osteogenesis assay, critical size calvarial defects repair assay, osteoporosis treatment and experimental colitis therapy assay strongly certified that melatonin preserved the therapeutic effect of long-term passaged BMMSCs on bone regeneration and immunotherapy in vivo. Mechanistically, melatonin functioned by activating antioxidant defense system, inhibiting the pathway of cell senescence, and preserving the expression of gene governing the stemness. Taken together, our findings showed that melatonin treatment efficiently prevented the dysfunction and therapeutic failure of BMMSCs after long-term passaging, providing a practical strategy to improve the application of BMMSCs in tissue engineering and cytotherapy.

FOXF2 (forkhead box F2) is a mesenchyme-specific transcription factor that plays a critical role in tissue homeostasis through the maintenance of epithelial polarity. In a previous study, we demonstrated that FOXF2 is specifically expressed in basal-like breast cancer (BLBC) cells and functions as an epithelial-mesenchymal transition suppressor. FOXF2 deficiency enhances the metastatic ability of BLBC cells through activation of the epithelial-mesenchymal transition program, but reduces cell proliferation. In this study, we demonstrate that CpG island methylation of the FOXF2 proximal promoter region is involved in the regulatory mechanism of the subtype-specific expression of FOXF2 in breast cancer cells. DNMT1, DNMT3A, and DNMT3B commonly or individually contributed to this DNA methylation in different breast cancer cells. SP1 regulated the transcriptional activity of FOXF2 through direct binding to the proximal promoter region, whereas this binding was abrogated through DNA methylation. FOXF2 mediated the SP1-regulated suppression of progression and promotion of proliferation of non-methylated BLBC cells. Thus, we conclude that the subtype-specific expression and function of FOXF2 in breast cancer cells are regulated through the combined effects of DNA methylation and SP1 transcriptional regulation.

Obstructive renal injury and drug-induced nephrotoxicity are the two most common causes of renal fibrosis diseases. However, whether these two different pathogeny induced same pathological outcomes contain common genetic targets or signaling pathway, the current research has not paid great attention. GSE121190 and GSE35257 were downloaded from the Gene Expression Omnibus (GEO) database. While GSE121190 represents a differential expression profile in kidney of mice with unilateral ureteral obstruction (UUO) model, GSE35257 represents cisplatin nephrotoxicity model. By using GEO2R, 965 differential expression genes (DEGs) in GSE121190 and 930 DEGs in GSE35257 were identified. 43 co-DEGs were shared and were extracted for protein-protein interaction (PPI) analysis. Subsequently, three shared pathways including glycolysis/gluconeogenesis, fatty acid degradation and pathways in cancer were involved in two models with Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We reconfirmed that these three pathways have relatively high scores by using Gene Set Enrichment Analysis (GSEA) software. Additionally, further bioinformatic analysis showed that Aldehyde dehydrogenase-2 (Aldh2) involved in the progression of renal fibrosis by mediating glycolysis pathway. Then real-time PCR and western blotting were performed to validate the expression of Aldh2 in kidney tissue after three different etiologies that caused renal fibrosis. Basically consistent with our bioinformatics results, our experiment showed that the expression of Aldh2 is the most significantly decreased in the UUO model, followed by ischemia-reperfusion injury (IRI) model and finally the cisplatin-induced model. Thus, Aldh2 can act as a common potential genetic target for different renal fibrosis diseases.

Vitamin D (VitD) comes from sunlight exposure and food intake. Apart from regulating calcium homeostasis and bone function, its levels also associate with the presence of development of adenocarcinoma. VitD can interact with VitD receptor (VDR), which heterodimerizes with retinoic X receptor (RXR) and then induces transcription of proteins that function in cell proliferation, differentiation, apoptosis, and angiogenesis. We reviewed and discussed the genes and their associated polymorphisms involved in the correlation between development of adenocarcinoma and VitD deficiency to highlight how VitD may be instrumental in cancerization. Furthermore, pilot epidemiological data show that the detection of 25-hydroxy-Vitamin D 3 ((36.5±10.7 nmol/L, n=129) vs (81.4±19.8 nmol/L, n=81)) can be a promising approach in cancer diagnosis. In this review, we suggest that 25-hydroxy-Vitamin D 3 can act as an indicator and/or risk assessment factor in early diagnosis, prognosis and treatment of adenocarcinoma.

Myc-associated zinc finger protein (MAZ) is a transcription factor with C2H2-type zinc-finger motifs that can bind GC-rich cis-elements. MAZ activates the transcription of some cancer-related genes and represses that of others, suggesting that changes in MAZ expression may play different roles in the development and progression of different types or subtypes of cancers depending on its target genes. However, the functions and mechanisms of MAZ in regulating the carcinogenesis and progression of breast cancer have remained unclear. In the current study, we show that MAZ performs dual function in basal-like breast cancer (BLBC): suppression of aggressiveness and promotion of proliferation. Forkhead box F2 (FOXF2) is a novel transcription target of MAZ and mediates the functions of MAZ. The MAZ mRNA level, particularly in combination with the FOXF2 mRNA level, may serve as a prognostic marker for BLBC patients. Our results indicate that the dual function of the MAZ-FOXF2 axis reflect the pleiotropic nature of multifunctional transcription factors in regulating the different stages of cancer development and progression, which could lead to the complexity of cancer diagnosis and treatment.

Cutaneous wounds are among the most common soft tissue injuries. Wounds involving dermis suffer more from outside influence and higher risk of chronic inflammation. Therefore the appearance and function restoration has become an imperative in tissue engineering research. In this study, cell-aggregates constructed with green fluorescent protein-expressing (GFP+) rat bone marrow mesenchymal stem cells (BMMSCs) were applied to rat acute full-layer cutaneous wound model to confirm its pro-regeneration ability and compare its regenerative efficacy with the currently thriving subcutaneous and intravenous stem cell administration strategy, with a view to sensing the advantages, disadvantages and the mechanism behind. According to results, cell-aggregates cultured in vitro enjoyed higher expression of several pro-healing genes than adherent cultured cells. Animal experiments showed better vascularization along with more regular dermal collagen deposition for cell-aggregate transplanted models. Immunofluorescence staining on inflammatory cells indicated a shorter inflammatory phase for cell-aggregate group, which was backed up by further RT-PCR. The in situ immunofluorescence staining manifested a higher GFP+-cell engraftment for cell-aggregate transplanted models versus cell administered ones. Thus it is safe to say the BMMSCs aggregate could bring superior cutaneous regeneration for full layer cutaneous wound to BMMSCs administration, both intravenous and subcutaneous.

MicroRNAs (miRNAs) emerge as important regulators of stem cell lineage commitment and bone development. MiRNA-26a (miR-26a) is one of the important miRNAs regulating osteogenic differentiation of both bone marrow-derived mesenchymal stem cells (BMSCs) and adipose tissue-derived mesenchymal stem cells (ADSCs). However, miR-26a functions oppositely in osteogenic differentiation of BMSCs and ADSCs, suggesting distinct post-transcriptional regulation of tissue-specific MSC differentiation. However, the molecular basis is largely unknown. Here, we report that the function of miR-26a is largely depended on the intrinsic signaling regulation network of MSCs. Using bioinformatics and functional assay, we confirmed that miR-26a potentially targeted on GSK3β and Smad1 to regulate Wnt and BMP signaling pathway. Overall comparative analysis revealed that Wnt signaling was enhanced more potently and played a more important role than BMP signaling in osteogenic differentiation of BMSCs, whereas BMP pathway was more essential for promoting osteogenic differentiation of ADSCs. The distinct activation pattern and role of signaling pathways determined that miR-26a majorly targeted on GSK3β to activate Wnt signaling for promoting osteogenic differentiation of BMSCs, whereas it inhibited Smad1 to suppress BMP signaling for interfering with the osteogenic differentiation of ADSCs. Taken together, our study demonstrated that BMSCs and ADSCs applied different signaling pathway to facilitate their osteogenic differentiation, which determined the inverse function of miR-26a. The distinct transcriptional regulation and post-transcriptional regulation network suggested the intrinsic molecular differences between tissue-specific MSCs and the complexity in MSC research and MSC-based cell therapy.

Decline of antioxidant defense after estrogen deficiency leads to oxidative damage in bone marrow-derived mesenchymal stem cells (BMMSCs), resulting a defect of bone formation in osteoporosis. Forkhead box O1 (FoxO1) protein is crucial for defending physiological oxidative damage in bone. But whether FoxO1 is involved in the oxidative damage during osteoporosis is largely unknown. In this study, we found that FoxO1 protein accumulation was decreased in BMMSCs of ovariectomized mice. The decrease of FoxO1 resulted in the suppression of manganese superoxide dismutase (Sod2) and catalase (Cat) expression and accumulation of reactive oxygen species (ROS), inhibiting the osteogenic differentiation of BMMSCs. The decline of FoxO1 protein was caused by tumor necrosis factor-alpha (TNF-α) accumulated after estrogen deficiency. Mechanistically, TNF-α activated NF-κB pathway to promote microRNA-705 expression, which function as a repressor of FoxO1 through post-transcriptional regulation. Inhibition of NF-κB pathway or knockdown of miR-705 largely prevented the decline of FoxO1-mediated antioxidant defense caused by TNF-α and ameliorated the oxidative damage in osteoporotic BMMSCs. Moreover, the accumulated ROS further activated NF-κB pathway with TNF-α, which formed a feed-forward loop to persistently inhibiting FoxO1 protein accumulation in BMMSCs. In conclusion, our study revealed that the decline of FoxO1 is an important etiology factor of osteoporosis and unclosed a novel mechanism of FoxO1 regulation by TNF-α. These findings suggested a close correlation between inflammation and oxidative stress in stem cell dysfunction during degenerative bone diseases.

During osteoporosis, the shift of mesenchymal stem cell (MSC) lineage commitment to adipocyte leads to the imbalance between bone mass and fat, which increases the risk of fracture. The Enhancer of Zeste homology 2 (EZH2), which methylates histone H3 on lysine 27 (H3K27me3), controls MSC cell lineage commitment. However, whether EZH2 is related to osteoporosis remains elusive. In our study, we found EZH2 expression was significantly increased in osteoporotic MSCs. EZH2 directly increased H3K27me3 levels on promoters of Wnt1, Wnt6, and Wnt10a to silence Wnt gene transcription. The inhibition of Wnt/β-catenin signaling shifted MSC cell lineage commitment to adipocyte. Knockdown of EZH2 by lentivirus-expressing shRNA rescued the abnormal fate of osteoporotic MSC. By employing the H3K27me3 inhibitor DZNep, we effectively derepressed Wnt signaling and improved osteogenic differentiation of osteoporotic MSCs in vitro. Furthermore, in vivo administration of DZNep successfully increased bone formation and repressed excessive bone marrow fat formation in osteoporotic mice. Noteworthy, DZNep treatment persistently enhanced osteogenic differentiation of endogenous MSCs. In conclusion, our study demonstrated that redundant EZH2 shifted MSC cell lineage commitment to adipocyte, which contributed to the development of osteoporosis. We also provided EZH2 as a novel therapeutic target for improving bone formation during osteoporosis.

Background The cause of almost all cases of Parkinson’s disease (PD) remains unknown. Recent years have seen an explosion in the rate of discovery of genetic defects linked to PD. Different racial and geographical populations may have different distributions of genetic variants. Methods In the current study, we screened the following genetic variants, including some rare mutations and single nucleotide polymorphisms (SNPs), in a pedigree and cases-controls. To best of our knowledge, we first screened these variants known to be associated with neurodegeneration disease, E46K (rs104893875) in SNCA, A1442P in LRRK2, IVS9 in PARK2, A350V in SLC41A1, P268S (rs2066842), R702W (rs2066844), G908R (rs2066845), 1007fs (rs2066847) in NOD2 and G2385R (rs34778348) in LRRK2 from southern China population. Genotyping was performed by jointly using primers overlapping polymerase chain reaction (PCR) site-directed mutagenesis, restriction fragment length polymorphism (RFLP), and capillary electrophoresis (CE). Results We didn’t discover above 9 variants in the family members of the pedigree. Furthermore, of 237 patients with sporadic Parkinson’s disease and 190 controls, no heterozygosity or homozygosity were found from E46K, A1442P, A350V, R702W, G908R, or 1007fs but heterozygosity onto G2385R, IVS9, and P268S. No significant difference between cases and controls was found in both allele frequency (P = 0.572) and genotype frequency (P = 0.348) of IVS9. However, significant differences in genotype frequency (P = 0.009) of G2385R were consistent with prior observation. Eight patients with Parkinson’s disease (2 women and 6 men are over the age of 50 years at onset of PD) carried the P268S heterozygous variation in NOD2. There was no heterozygosity or homozygosity of P268S in the controls. Genotype frequency of P268S (P = 0.0450) had significant differences. Conclusions Our results suggested that the P268S variant in NOD2 might be a risk factor for susceptibility to sporadic Parkinson’s disease in Chinese populations. It also implied that the inflammatory response may play a role in PD.

Background The histopathological and molecular heterogeneity of normal tissue adjacent to cancerous tissue (NTAC) and normal tissue adjacent to benign tissue (NTAB), and the availability of limited specimens make deciphering the mechanisms of carcinogenesis challenging. Our goal was to identify histogenetic biomarkers that could be reliably used to define a transforming fingerprint using RNA in situ hybridization. Methods We evaluated 15 tumor-related RNA in situ hybridization biomarkers using tumor microarray and samples of seven tumor-adjacent normal tissues from 314 patients. Biomarkers were determined using comprehensive statistical methods (significance of support vector machine-based artificial intelligence and area under curve scoring of classification distribution). Results TP53 was found to be a most reliable index (P -7; area under curve >87%) for distinguishing NTAC from NTAB, according to the results of a significance panel (BCL10, BECN1, BRCA2, FITH, PTCH11 and TP53). Conclusions The genetic alterations in TP53 between NTAC and NTAB may provide new insight into the field of cancerization and tumor transformation.