Abstract-Aging is a major risk factor for hypertension and cardiovascular disease. Accumulating evidence suggests that telomere length is a marker for biological aging of the cardiovascular system. Telomere length is determined by genetic and environmental factors. Studies in different racial populations are required to determine the prognostic value of telomere length in hypertension and cardiovascular diseases. The main objective of this study was to investigate the association between leukocyte telomere length and the risk and prognosis of hypertension in a Chinese population. A ging is a major risk factor for hypertension. Epidemiological studies have suggested that, relative to normotensive subjects, hypertensive subjects are at higher risk for the development of cardiovascular and cerebrovascular diseases than normotensive subjects. However, there is wide variation in the occurrence and manifestation of cardiovascular and cerebrovascular diseases in hypertensive patients, even in individuals with the same risk factor profiles. The reason for this interindividual variation is largely unknown but may be reflective of the variation in the rate of biological aging. 1 Telomere shortening represents one molecular mechanism that appears to contribute to cellular and organismal aging. Telomeres are specialized structures located at the ends of eukaryotic chromosomes. The main function of telomeres is to cap the chromosomal ends and to maintain genome stability and integrity. 2 When telomeres reach a critical short length, they lose capping function at the chromosomal ends, resulting in activation of DNA damage checkpoints. These checkpoints limit cell survival by induction of senescence or apoptosis. Telomere shortening limits the life span of human cells in culture 3 and occurs in various tissues during human aging. 4 Studies in mouse models have demonstrated a crucial role of telomere shortening in the impairment of the stem cell during organismal aging. 5,6 Studies in telomerase-deficient mice have also shown a direct link between telomere shortening and hypertension. 7 In humans, telomere shortening and cellular senescence have also been correlated with atherosclerosis and cardiovascular aging. 8 -10 Indeed, epidemiological studies have suggested that age-dependent telomere shortening could be used as a marker for essential hypertension 11,12 and related diseases or syndromes, such as insulin resistance, 13 diabetes mellitus, 14 obesity, 15 atherosclerosis, 16,17 coronary artery disease, 18,19 myocardial infarction, 20 and renal dysfunction. 21 Telomere length is determined by genetic 22-24 and environmental factors. [25][26][27][28] Differences in leukocyte telomere length have been observed between blacks and whites. 29 In addition,

Nasopharyngeal carcinoma (NPC) is one of the most frequent head and neck malignant tumors and is majorly treated by radiotherapy. However, radiation resistance remains a serious obstacle to the successful treatment of NPC. The aim of this study was to discover the underlying mechanism of radioresistance and to elucidate novel genes that may play important roles in the regulation of NPC radiosensitivity. By using RNA-seq analysis of NPC cell line CNE2 and its radioresistant cell line CNE2R, lncRNA CASC19 was screened out as a candidate radioresistance marker. Both in vitro and in vivo data demonstrated that a high expression level of CASC19 was positively correlated with the radioresistance of NPC, and the radiosensitivity of NPC cells was considerably enhanced by knockdown of CASC19. The incidence of autophagy was enhanced in CNE2R in comparison with CNE2 and another NPC cell line HONE1, and silencing autophagy with LC3 siRNA (siLC3) sensitized NPC cells to irradiation. Furthermore, CASC19 siRNA (siCASC19) suppressed cellular autophagy by inhibiting the AMPK/mTOR pathway and promoted apoptosis through the PARP1 pathway. Our results revealed for the first time that lncRNA CASC19 contributed to the radioresistance of NPC by regulating autophagy. In significance, CASC19 might be a potential molecular biomarker and a new therapeutic target in NPC.

Glioblastoma (GBM) is the most common type of primary tumor in central nervous system in adult with a 5-year survival rate of ≤5%. Despite of recent advances in tumor radiotherapy, the prognosis of GBM remains to be dismal due to radioresistance. In this study, we identified CD81 as a potential biomarker of GBM radioresistance with the analysis of upregulated genes in human glioma radioresistant cell lines U251R and T98G in comparison with U251 cells. In vitro and in vivo experiments demonstrated that suppressing CD81 by siRNA/shRNA enhanced radiation-induced cell killing and DNA damage of γ-H2AX formation, and delayed tumor xenograft growth of GBM. Mechanistically, we found that knockdown of CD81 significantly decreased radiation-induced expression of nuclear Rad51, a key protein involved in homologous recombination repair (HRR) of DNA, suggesting that CD81 is essential for DNA damage response. Meanwhile, when the cells were treated with B02, a Rad51 inhibitor, silencing CD81 would not sensitize GBM cells to radiation, which further illustrates that Rad51 acts as an effector protein of CD81 in tumor radioresistance. Dual immunofluorescence staining of CD81 and Rad51 illustrated that nuclear membrane CD81 contributed to the nuclear transport of Rad51 after irradiation. In conclusion, we demonstrated for the first time that CD81 not only played a vital role in DNA repair through regulating Rad51 nuclear transport, but also might serve as a potential target of GBM radiotherapy.

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Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Radiotherapy has long been an important treatment method of GBM. However, the intrinsic radioresistance of GBM cells is a key reason of poor therapeutic efficiency. Recently, many studies have shown that using the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) in radiotherapy may improve the prognosis of GBM patients, but the underlying molecular mechanisms remain unclear. In this study, Gene Expression Omnibus (GEO) datasets GSE153982 and GSE131956 were analyzed to evaluate radiation-induced changes of gene expression in GBM without or with SAHA treatment, respectively. Additionally, the survival-associated genes of GBM patients were screened using the Chinese Glioma Genome Atlas (CGGA) database. Taking the intersection of these three datasets, 11 survival-associated genes were discovered to be activated by irradiation and regulated by SAHA. The expressions of these genes were further verified in human GBM cell lines U251, T98G, and U251 homologous radioresistant cells (U251R) by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). It was found that MMP14 mRNA was considerably highly expressed in the radioresistant cell lines and was reduced by SAHA treatment. Transfection of MMP14 siRNA (siMMP14) suppressed cell survivals of these GBM cells after irradiation. Taken together, our results reveal for the first time that the MMP14 gene contributed to SAHA-induced radiosensitization of GBM.

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Radioresistance remains a serious obstacle encountered in the radiotherapy of nasopharyngeal carcinoma (NPC). Both mRNAs and non-coding RNAs (ncRNAs), including long ncRNA (lncRNA) and microRNA (miRNA), play essential roles in radiosensitivity. However, the comprehensive expression profiles and competing endogenous RNA (ceRNA) regulatory networks among lncRNAs, miRNAs, and mRNAs in NPC radioresistance are still bewildering. In this study, we performed an RNA-sequencing (RNA-seq) assay in the radioresistant NPC cells CNE2R and its parental cells CNE2 to identify the differentially expressed lncRNAs, miRNAs, and mRNAs. The ceRNA networks containing lncRNAs, miRNAs, and mRNAs were predicted on the basis of the Pearson correlation coefficients and authoritative miRanda databases. In accordance with bioinformatic analysis of the data of the tandem mass tag (TMT) assay of CNE2R and CNE2 cells and the gene chip assay of radioresistant NPC samples in pre- and post-radiotherapy, the radioresistance-related signaling network of lncRNA CASC19, miR-340-3p, and FKBP5 was screened and further verified using an RT-qPCR assay. CASC19 was positively associated with FKBP5 expression while negatively correlated with miR-340-3p, and the target binding sites of CASC19/miR-340-3p and miR-340-3p/FKBP5 were confirmed using a dual-luciferase reporter assay. Moreover, using an mRFP–GFP–LC3 maker, it was found that autophagy contributed to the radioresistance of NPC. MiR-340-3p inhibition or FKBP5 overexpression could rescue the suppression of autophagy and radioresistance induced by CASC19 knockdown in CNE2R cells. In conclusion, the CASC19/miR-340-3p/FKBP5 network may be instrumental in regulating NPC radioresistance by enhancing autophagy, which provides potential new therapeutic targets for NPC.