Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Accumulating evidence has confirmed the links between transfer RNA (tRNA) modifications and tumor progression. The present study is the first to explore the role of tRNA methyltransferase 5 (TRMT5), which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma (HCC) progression. Here, based on bioinformatics and clinical analyses, we identified that TRMT5 expression was upregulated in HCC, which correlated with poor prognosis. Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro, which may be partially explained by declined extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Mechanistically, we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1 (HIF-1) signaling pathway by preventing HIF-1α stability through the enhancement of cellular oxygen content. Moreover, our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-‍1α. In conclusion, our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs. Thus, TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.

Positive Association Between Type 2 Diabetes Risk Alleles Near CDKAL1 and Reduced Birthweight in Chinese Han Individuals / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Fetal insulin hypothesis was proposed that the association between low birth weight and type 2 diabetes is principally genetically mediated. The aim of this study was to investigate whether common variants in genes CDKAL1, HHEX, ADCY5, SRR, PTPRD that predisposed to type 2 diabetes were also associated with reduced birthweight in Chinese Han population.</p><p><b>METHODS</b>Twelve single nucleotide polymorphisms (rs7756992/rs10946398 in CDKAL1, rs1111875 in HHEX, rs391300 in SRR, rs17584499 in PTPRD, rs1170806/rs9883204/rs4678017/rs9881942/rs7641344/rs6777397/rs6226243 in ADCY5) were genotyped in 1174 unrelated individuals born in Peking Union Medical College Hospital from 1921 to 1954 by TaqMan allelic discrimination assays, of which 645 had normal glucose tolerance, 181 had developed type 2 diabetes and 348 impaired glucose regulation. Associations of these 12 genetic variants with birthweight and glucose metabolism in later life were analyzed.</p><p><b>RESULTS</b>Birthweight was inversely associated with CDKAL1-rs10946398 (β = -41 g [95% confidence interval [CI]: -80, -3], P = 0.034), common variants both associated with increased risk of impaired glucose metabolism and decreased insulin secretion index later in life. After adjusting for sex, gestational weeks, parity and maternal age, the risk allele of CDKAL1-rs7756992 was associated with reduced birthweight (β = -36 g [95% CI: -72, -0.2], P = 0.048). The risk allele in SRR showed a trend toward a reduction of birthweight (P = 0.085).</p><p><b>CONCLUSIONS</b>This study identified the association between type 2 diabetes risk variants in CDKAL1 and birthweight in Chinese Han individuals, and the carrier of risk allele within SRR had the trend of reduced birthweight. This demonstrates that there is a clear overlap between the genetics of type 2 diabetes and fetal growth, which proposes that lower birth weight and type 2 diabetes may be two phenotypes of one genotype.</p>

Association analysis of genetic polymorphisms of TCF7L2, CDKAL1, SLC30A8, HHEX genes and microvascular complications of type 2 diabetes mellitus / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To study the associations of single nucleotide polymorphisms (SNPs) of TCF7L2, CDKAL1, SLC30A8, HHEX with diabetic retinopathy (DR) and nephropathy (DN) in type 2 diabetes mellitus.</p><p><b>METHODS</b>A total of 479 subjects with DR,248 with DN and 650 without DR or DN were recruited to assess the associations between SNPs of TCF7L2 (rs7903146, rs6585205, rs11196218), CDKAL1 (rs10946398,rs4712527), SLC30A8 (rs13266634, rs3802177, rs11558471) and HHEX (rs1111875, rs7923837) and the development of DR and DN.</p><p><b>RESULTS</b>There were significant differences in genotypic and allele frequencies of rs11558471 (SLC30A8) between DR and control groups (P< 0.05), the odds ratio (OR) values of A and AA were 1.27 and 1.68. The distributions of genotype and allele frequency for rs11196218 (TCF7L2) were significantly different between DN and control group (P=0.0051,OR=1.37). However, the P value after Bonferroni correction showed no significant difference. No significant differences were found in the distributions of rs13266634 and rs3802177 (SLC30A8), rs10946398 (CDKAL1), rs6585205, rs7903146 and rs11196218 (TCF7L2) and rs7923837 (HHEX) between DR and control groups, and nor significant differences were found in distributions of rs6585205 (TCF7L2), rs4712527 (CDKAL1), rs13266634, rs3802177 and rs11558471 (SLC30A8), and 7923837 (HHEX) between DN and control groups, though for all comparison the OR values were greater than 1.</p><p><b>CONCLUSION</b>Polymorphisms of SLC30A8 and TCF7L2 genes may be associated with the development of DR and DN, respectively. Association between the polymorphisms of CKDAL1, TCF7L2 and HHEX genes and DR, and between the polymorphisms of SLC30A8, HHEX and CDKAL1 genes and DN, cannot be excluded.</p>

Preparation, crystallization and preliminary X-ray diffraction analysis of PH1948, predicted RNA methyltransferase from Pyrococcus horikoshii / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

RNA methyltransferase is responsible for transferring methyl and resulting in methylation on the bases or ribose ring of RNA, which existed widely but mostly remains an open question. A recombinant protein PH1948 predicting RNA methyltransferase from Pyrococcus horikoshii OT3 has been crystallized. The crystals of selenomethionyl PH1948 belong to space group C2, with unit-cell parameters a=207.0 A, b=43.1 A, c=118.2 A, b=92.1 degrees , and diffract X-rays to 2.2 A resolution. The V(M) value was determined to be 2.8 A3/Da, indicating the presence of four protein molecules in the asymmetric unit.

Transfer RNA nucleoside composition in 13762 rat adenocarcinoma

Abnormalities in patterns of RNA methylation and in the activities of tRNA methyltransferases are well-documented phenomena. In this study, we focused our attention on tRNA from adenocarcinoma, a 9,10-dimethyl-1,2-benznthracene-induced mammary tumor, because prior evidence has suggested the occurence of an abnormal pattern of tRNA methylation. Chemical postlabeling of tumor vs normal rat liver and mammary gland tRNAs revealed tumor specific differences in the modified nucleoside distribution, i.e., a 5.8-fold increase in tumor n-2-methylguanosine together with a 2.7-,2.8-,2.6-, and 2.8-fold decrease in tumor 1-methyladenosine, dihydrouridine, pseudoridine and 5-methylcytidyne, respectively. Class A tRNAs, a slower gel migrating group of tumor tRNAs, exhibited even lower 1-methyladenosine levels. Most of the remaining nucleosides in class A tRNAs showed molar ratios similar to those found in bulk tumor tRNA. However, N-2-methylguanosine levels class A tRNA are intermediate between bulk tumor tRNA (2.8%) and mammary gland tRNA (0.49%). The only qualitative difference found in tumor tRNA seems to be the absence of inosine usually present in tRNAs from liver and mammary tissues. In spite of its abnormal methylation pattern adenocarcinoma tRNA binds to glucocorticoid receptor protein from mouse AtT-20 cells, generating a 65 tRNA-protein complex, in a fashion similar to that previously described for the endogenous tRNA isolated from the same cells