Proliferation and metastasis are important malignant features of pancreatic cancer (PC), but the underlying molecular mechanism is unclear. ZC3HAV1, a PARP family member of proteins-enzymes, has been considered to play a significant part in a variety of biological processes. Nonetheless, the functions of ZC3HAV1 in developing PC are still unknown. This research aims to explore the biological function and the expression of ZC3HAV1 shown in PC. In our study, PCR analysis suggested that ZC3HAV1 was expressed at a high level in PC tissues and cell lines, and high ZC3HAV1 expression was remarkably related to poor prognosis. The functional assays indicated that upregulated ZC3HAV1 accelerated PC cell proliferation along with colony formation capacities in vitro. Subsequently, ZC3HAV1 could upregulate cyclin D1 and CDK2 and also promote G1/S transition in cells of PC. What's more, we also discovered that ZC3HAV1 promotes the migration and the invasion of PC cells. It upregulates the expression of EMT (epithelial-mesenchymal transition) relevant markers. Conversely, the functional assays showed that ZC3HAV1 knockdown significantly reduced tumorigenesis. Using bioinformatics analysis and immunoprecipitation assays we found that ZC3HAV1 could directly bind to KRAS and positively regulate its expression. Furthermore, ZC3HAV1 overexpression activated MAPK signaling by increasing p-ERK levels. Conversely, knockdown of KRAS attenuated ZC3HAV1-mediated promotion of proliferation and invasion in cells of PC. The result indicated that ZC3HAV1 was in relation to poor prognosis and accelerated the proliferation and metastasis of PC cells by regulation of KRAS. Our research may offer brand-new evidence to diagnose and treat PC in clinic.

Breast cancer is one of the leading causes of cancer-associated mortality in women worldwide and has become a major public health problem. Although the definitive cause of breast cancer is not known, many genes sensitive to breast cancer have been detected using advanced technologies. Our study identified 3301 differentially expressed lncRNAs and mRNAs between tumor and normal samples from The Cancer Genome Atlas database. Based on the gene expression analysis and clinical traits as well as weighted gene co-expression network analysis, the co-expression Brown module was found to be key for breast cancer prognosis. A total of 453 genes in the Brown module were used for functional enrichment, protein-protein interaction analysis, lncRNA-miRNA-mRNA ceRNA network, and lncRNA-RNA binding protein-mRNA network construction. GRM4, SSTR2, PARD6B, PRR15, COX6C, and lncRNA DSCAM-AS1 were the hub genes according to protein-protein interaction, lncRNA-miRNA-mRNA and lncRNA-RNA binding protein-mRNA network. Their high expression was found to be correlated with breast cancer development, according to multiple databases. In conclusion, this study provides a framework of the co-expression gene modules of breast cancer and identifies several important biomarkers in breast cancer development and prognosis.

Capability of tumor cells to impede immune response are largely associated with their interaction and regulation of CD4+CD25+ forkhead box transcription factor (Foxp)3+ regulatory T (Treg) cells, which suppress cytotoxic T cell-mediated immunity in the tumor microenvironment. Foxp3 level is critical for development and phenotypic maintenance of Treg, and is regulated by transcriptional control and epigenetic modification. Here, we showed that higher percentage of intratumoral Treg cells was positively correlated with lower Foxp3 promoter methylation in hepatocellular carcinoma (HCC), and both of them were associated with higher tumor grade, larger tumors, and poor prognosis of the patients. We used an adeno-associated virus (AAV) carrying either DNA (cytosine-5)-methyltransferase 1 (DNMT1) or shDNMT1 under a CD4 promoter (AAV-pCD4-DNMT1, AAV-pCD4-shDNMT1) to successfully target T-cells and alter the levels of DNMT1. Intratumoral injection of AAV- pCD4-DNMT1 significantly reduced tumor growth in mice, while intratumoral injection of AAV- pCD4-DNMT1 significantly induced tumor growth, compared to injection of control AAV. Finally, the effects of altering DNMT1 levels in T-cells seemed to affect tumor growth through alteration of methylation status of Foxp3 on promoter and CpG regions. Together, these data suggest that epigenetic control of Foxp3 in intratumoral T cells regulates growth of HCC.

The management of stage II colorectal cancer is still difficult. We aimed to construct a new immune cell-associated signature for prognostic evaluation and guiding chemotherapy in stage II colorectal cancer. We used the "Cell Type Identification by Estimating Relative Subsets of RNA Transcripts" (CIBERSORT) method to estimate the fraction of 22 immune cells by analyzing bulk tumor transcriptomes and a LASSO Cox regression model to select the prognostic immune cells. A 12-immune cell prognostic classifier, ISCRC, was built, which could successfully discriminate the high-risk patients in the training cohort (GSE39582: HR = 3.16, 95% CI: 1.85-5.40, P < 0.0001) and another independent cohorts (GSE14333: HR = 3.47, 95% CI: 1.18-10.15, P =0.0167). The receiver operating characteristic analysis revealed that the AUC of the ISCRC model was significantly greater than that of oncotypeDX model (0.7111 versus 0.5647, p=0.0152). We introduced the propensity score matching analysis to eliminate the selection bias; survival analysis showed relatively poor prognosis after chemotherapy in stage II CRC patients. Furthermore, a nomogram was built for clinicians and did well in the calibration plots. In conclusion, this immune cell-based signature could improve prognostic prediction and may help guide chemotherapy in stage II colorectal cancer patients.

Previously, we elucidated the function of flotilin-2 (FLOT2) and branched-chain amino acid transaminase 1(BCAT1) in nasopharyngeal carcinoma (NPC). However, the relationship between FLOT2 and BCAT1 in promoting NPC progression remains unknown. Here, we observed that FLOT2 upregulated BCAT1 expression in NPC cells. Ectopic expression of BCAT1 significantly antagonized the inhibitory effects on NPC cell proliferation induced by FLOT2 depletion. Consequently, BCAT1 knockdown markedly inhibited the pro-proliferative effects of FLOT2 overexpression in NPC cells. FLOT2 expression was positively correlated with BCAT1 expression in NPC tissues and was inversely correlated with the prognosis of NPC patients. Mechanistically, FLOT2 maintains the expression level of c-Myc, a positive transcription factor of BCAT1, and subsequently promote BCAT1 transcription. FLOT2 inhibited miR-33b-5p in NPC cells and attenuated its inhibitory effects on c-Myc. Further, experimental validation of the function of the FLOT2/miR-33b-5p/c-Myc/BCAT1 axis in regulating NPC cell proliferation was performed. Our results revealed that FLOT2 promotes NPC cell proliferation by suppressing miR-33b-5p, to maintain proper levels of c-Myc, and upregulate BCAT1trancription. Therefore, the FLOT2/miR-33b-5p/c-Myc/BCAT1 axis is a potential therapeutic target for NPC.

Recently, an increasing number of studies have reported that dysregulation of long noncoding RNAs (lncRNAs) plays an important role in cancer initiation and progression, including in epithelial ovarian carcinoma (EOC). However, little is known about the detailed biological functions of the lncRNA small nucleolar RNA host gene 22 (SNHG22) during the progression of EOC. Here, we found that SNHG22 was significantly increased in EOC tissues and was significantly associated with a low level of differentiation. Forced SNHG22 expression promoted chemotherapy resistance in EOC cells. Knockdown of SNHG22 expression increased the sensitivity of EOC cells to cisplatin and paclitaxel. Importantly, we found that SNHG22 could directly interact with miR-2467 and lead to the release of miR-2467-targeted Gal-1 mRNA. Moreover, SNHG22 overexpression induced EOC cell resistance to chemotherapy agents via PI3K/AKT and ERK cascade activation. In summary, our findings demonstrate that SNHG22 plays a critical role in the chemotherapy resistance of EOC by mediating the miR-2467/Gal-1 regulatory axis.

Emerging evidences has demonstrated that dysregulation of long non-coding RNAs (lncRNAs) is critically involved in esophageal squamous cell carcinoma (ESCC) progression. However, the function of lncRNA PSMA3-AS1 in ESCC is unclear. Therefore, we aimed to explore the functions and potential mechanisms of PSMA3-AS1 in ESCC cells progression.

Accumulative radiation exposure leads to hematopoietic or tissue aging. Whether hematopoietic stem cells (HSCs) are involved in lung damage repair in response to radiation remains controversial. The aim of this study is to identify if HSC can transdifferentiate to pneumonocytes for radiation-induced damage repair. To this end, HSCs from male RosamT/mG mice were isolated by fluorescence-activated cell sorting (FACS) and transplanted into lethally irradiated female CD45.1 mice. 4 months after transplantation, transplanted HSC was shown to repair the radiation-induced tissue damage, and donor-derived tdTomato (phycoerythrin, PE) red fluorescence cells and Ddx3y representing Y chromosome were detected exclusively in female recipient lung epithelial and endothelial cells. Co-localization of donor-derived cells and recipient lung tissue cells were observed by laser confocal microscopy and image flow cytometry. Furthermore, the results showed HSC transplantation replenished radiation-induced lung HSC depletion and the PE positive repaired lung epithelial cells were identified as donor HSC origin. The above data suggest that donor HSC may migrate to the injured lung of the recipient and some of them can be transdifferentiated to pneumonocytes to repair the injury caused by radiation.

The molecular mechanism of bone metastasis in breast cancer is largely unknown. Herein, we aimed to identify the key genes and long non-coding RNAs (lncRNAs) related to the bone metastasis of breast cancer using a bioinformatics approach. We screened differentially expressed genes and lncRNAs between normal breast and breast cancer bone metastasis samples using the GSE66206 dataset from the Gene Expression Omnibus. We also constructed a differentially expressed lncRNA-mRNA interaction network and analyzed the node degrees to identify the driving genes. After finding potential pathogenic modules of breast cancer bone metastasis, we identified breast cancer bone metastasis-related modules and functional enrichment analysis of the genes and lncRNAs in the modules. Based on the above analysis, we constructed a differentially expressed lncRNA-mRNA network related to bone metastasis in breast cancer and identified core driver genes, including BNIP3 and the lncRNA RP11-317-J19.1. The role of core driver genes and lncRNAs in the network implies their biological functions in regulating bone development and remodeling. Thus, targeting the core driver genes and lncRNAs in the network may be a promising therapeutic strategy to manage bone metastasis.

As the elderly population grows, chronic metabolic dysfunction including obesity and diabetes are becoming increasingly common comorbidities. Hypothalamic inflammation through CNS resident microglia serves as a common pathway between developing obesity and developing systemic aging pathologies. Despite understanding aging as a life-long process involving interactions between individuals and their environment, limited studies address the dynamics of environment interactions with aging or aging therapeutics. We previously demonstrated environmental enrichment (EE) is an effective model for studying improved metabolic health and overall healthspan in mice, which acts through a brain-fat axis. Here we investigated the CSF1R inhibitor PLX5622 (PLX), which depletes microglia, and its effects on metabolic decline in aging in interaction with EE. PLX in combination with EE substantially improved metabolic outcomes in middle-aged female mice over PLX or EE alone. Chronic PLX treatment depleted 75% of microglia from the hypothalamus and reduced markers of inflammation without affecting brain-derived neurotrophic factor levels induced by EE. Adipose tissue remodeling and adipose tissue macrophage modulation were observed in response to CSF1R inhibition, which may contribute to the combined benefits seen in EE with PLX. Our study suggests benefits exist from combined drug and lifestyle interventions in aged animals.

In this study, we obtained the RNA expression data of murine skin tissues of control, and UVB irradiated groups. After the re-annotation of lncRNAs, a gene expression similarity analysis was done by WGCNA. The target mRNA prediction of lncRNAs, miRNAs, and ceRNA regulatory networks were constructed by five lncRNAs, 14 miRNAs and 54 mRNAs, respectively. Based on the ceRNA network of UVB-induced skin lesions, it was evident that the dysregulation of Meg3 has critical effects on the UVB-induced inflammatory lesion of murine skin tissues. The overexpression of Meg3 after UVB irradiation was observed in primary murine skin fibroblasts, and the up-regulated Meg3 expression was related to the activation of the inflammatory cytokines. These functional experiments demonstrated that the RNA silencing of Meg3 in murine skin fibroblasts could suppress the expression of the cytokines (in vitro) and UVB-induced skin lesions (in vivo). Moreover, the Meg3 functioned as a competing endogenous RNA (ceRNA) that acted as a sponge for miR-93-5p and thereby modulated the expression of Epiregulin (Ereg). Our results proved that Meg3 was involved in UVB-induced skin inflammation and that the ceRNA networks, which includes miR-93-5p and Ereg, could prove to be a potential therapeutic target for UVB-induced skin damage.

With increases in life expectancy, it is vital to understand the dynamics of aging, their interaction with lifestyle factors, and the connections to age-related disease processes. Our work on environmental enrichment (EE), a housing environment boosting mental health, has revealed a novel anticancer and anti-obesity phenotype mediated by a brain-fat axis: the hypothalamic-sympathoneural-adipocyte (HSA) axis in young animals. Here we investigated EE effects on healthspan and lifespan when initiated after middle age. Short-term EE for six weeks activated the HSA axis in 10-month-old mice. Long-term EE for twelve months reduced adiposity, improved glucose tolerance, decreased leptin levels, enhanced motor abilities, and inhibited anxiety. In addition to adipose remodeling, EE decreased age-related liver steatosis, reduced hepatic glucose production, and increased glucose uptake by liver and adipose tissue contributing to the improved glycemic control. The EE-induced liver modulation was associated with a suppression of protein kinase Cε. Moreover, EE down-regulated the expression of inflammatory genes in the brain, adipose, and liver. EE initiated at 18-month of age significantly improved glycemic control and showed a trend of positive impact on mean lifespan. These data suggest that EE induces metabolic and behavioral adaptations that are shared by factors known to increase healthspan and lifespan.

Novel biomarkers are needed to accelerate the diagnosis and treatment of endometriosis. We performed RNA sequencing to explore the expression profiles of exosomal circular RNAs (circRNAs), microRNAs (miRNAs) and mRNAs in patients with ovarian endometriomas, eutopic endometria and normal endometria. Differentially expressed genes between the different pairs of groups were analyzed and functionally annotated. Then, miRNA-target RNA pairs were identified, competing endogenous RNA (ceRNA) scores were calculated, gene expression characteristics were determined, and these parameters were used to construct an exosomal ceRNA network. We identified 36 candidate hub genes with high degrees of gene connectivity. We also topologically analyzed the ceRNA network to obtain a hub ceRNA network of circRNAs with the highest closeness and ceRNA efficiency. Twelve genes overlapped between the 36 candidate hub genes and the genes in the hub ceRNA network. These 12 genes were considered to be exosomal RNA-based biomarkers, and circ_0026129/miRNA-15a-5p/ATPase H+ transporting V1 subunit A (ATP6V1A) were at the center of the ceRNA network. By determining the exosomal RNA expression profiles of endometriosis patients and constructing a circRNA-associated ceRNA network, these findings provide insight into the molecular pathways of endometriosis and new resources for its diagnosis and treatment.

Mechanical overloading-induced nucleus pulposus (NP) cells senescence plays an important role in the pathogenesis of intervertebral disc degeneration (IVDD). The silent mating type information regulator 2 homolog-1 (SIRT1)-mediated pathway preserves the normal NP cell phenotype and mitochondrial homeostasis under multiple stresses. We aimed to investigate the role of SIRT1 in IVDD by assessing the effects of SIRT1 overexpression on high-magnitude compression-induced senescence in NP cells. High-magnitude compression induced cellular senescence and mitochondrial dysfunction in human NP cells. Moreover, SIRT1 overexpression tended to alleviate NP cell senescence and mitochondrial dysfunction under compressive stress. Given the mitophagy-inducing property of SIRT1, activity of mitophagy was evaluated in NP cells to further demonstrate the underlying mechanism. The results showed that SIRT1-overexpression attenuated senescence and mitochondrial injury in NP cells subjected to high-magnitude compression. However, depletion of PINK1, a key mitophagic regulator, impaired mitophagy and blocked the protective role of SIRT1 against compression induced senescence in NP cells. In summary, these results suggest that SIRT1 plays a protective role in alleviating NP cell senescence and mitochondrial dysfunction under high-magnitude compression, the mechanism of which is associated with the regulation of PINK1-dependent mitophagy. Our findings may provide a potential therapeutic approach for IVDD treatment.

Atg7, a critical component of autophagy machinery, is essential for counteracting hematopoietic aging. However, the non-autophagic role of Atg7 on hematopoietic cells remains fundamentally unclear. In this study, we found that loss of Atg7, but not Atg5, another autophagy-essential gene, in the hematopoietic system reduces CD11b myeloid cellularity including CD11b+Ly6G+ and CD11b+Ly6G- populations in mouse bone marrow. Surprisingly, Atg7 deletion causes abnormally accumulated histone H3.1 to be overwhelmingly trapped in the cytoplasm in the CD11b+Ly6G-, but not the CD11b+Ly6G+ compartment. RNA profiling revealed extensively chaotic expression of the genes required in nucleosome assembly. Functional assays further indicated upregulated aging markers in the CD11b+Ly6G- population. Therefore, our study suggests that Atg7 is essential for maintaining proper nucleosome assembly and limiting aging in the bone marrow CD11b+Ly6G- population.

Kinesin family member C1 (KIFC1) is an essential member of the motor protein family, which is critically involved in various cellular events, such as mitosis, meiosis, and macromolecular transport, but also in carcinogenesis, malignant progression, and tumor recurrence.