YTHDF1 promotes breast cancer progression by facilitating FOXM1 translation in an m6A-dependent manner.

BACKGROUND: N6-methyladenosine (m6A) is the most common post-transcriptional modification at the RNA level. However, the exact molecular mechanisms of m6A epigenetic regulation in breast cancer remain largely unknown and need to be fully elucidated. METHODS:  The integrating bioinformatics analyses were used to screen clinical relevance and dysregulated m6A "reader" protein YTHDF1 in breast cancer from TCGA databases, which was further validated in a cohort of clinical specimens. Furthermore, functional experiments such as the CCK-8 assay, EdU assay, wound healing assay, transwell invasion assay and cell cycle assay were used to determine the biological role of YTHDF1 in breast cancer. RIP, m6A-IP, and CLIP assays were used to find the target of YTHDF1 and further verification by RT-qPCR, western blot, polysome profiling assay. The protein-protein interaction between YTHDF1 and FOXM1 was detected via co-immunoprecipitation. RESULTS: Our study showed that YTHDF1 was overexpressed in breast cancer cells and clinical tissues specimens. At the same time, the high expression level of YTHDF1 was positively correlated with tumor size, lymph node invasion, and distant metastasis in breast cancer patients. YTHDF1 depletion repressed the proliferation, invasion and epithelial-mesenchymal transformation (EMT) and induced G0/G1 phase cell cycle arrest of breast cancer cells in vitro and in vivo. We also demonstrated that FOXM1 is a target of YTHDF1. Through recognizing and binding to the m6A-modified mRNA of FOXM1, YTHDF1 accelerated the translation process of FOXM1 and promoted breast cancer metastasis. Whereas overexpression of FOXM1 in breast cancer cells partially counteracted the tumor suppressed effects caused by YTHDF1 silence, which further verified the regulatory relationship between YTHDF1 and FOXM1. CONCLUSION: Our study reveals a novel YTHDF1/FOXM1 regulatory pathway that contributes to metastasis and progression of breast cancer, suggesting that YTHDF1 might be applied as a potential biomarker and therapeutic target. That also advances our understanding of the tumorigenesis for breast cancer from m6A epigenetic regulation.

TERT rs10069690 polymorphism and cancers risk: A meta-analysis.

BACKGROUND: Studies have identified that the telomerase reverse transcriptase (TERT) gene polymorphism rs10069690 (C>T) is associated with cancer risk, but the results remain inconclusive. METHODS: To provide a more precise estimation of the relationship, we performed a meta-analysis of 45 published studies including 329,035 cases and 730,940 controls. We conducted a search in PubMed, Google Scholar and Web of Science to select studies on the association between rs10069690 and cancer risk. Stratification by ethnicity, cancer type, cancers' classification, source of control, sample size, and genotype method was used to explore the source of heterogeneity. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were evaluated using random effects models. Sensitivity, publication bias, false-positive report probability (FPRP) and statistical power were also assessed. RESULTS: The result demonstrated that rs10069690 was significantly associated with an increased risk of cancer overall (OR = 1.09, 95% CI: 1.06-1.12, p < .001) under the allele model. Stratification analysis revealed an increased cancer risk in subgroups of breast cancer, ovarian cancer, lung cancer, thyroid cancer, and renal cell carcinoma (RCC). However, a significantly decreased association was observed in pancreatic cancer in the European population (OR = 0.93,95% CI: 0.87-0.99, p = .031). In the subgroup analysis based on cancer type, no significant association was found in prostate cancer, leukemia, colorectal cancer and glioma. CONCLUSIONS: This meta-analysis suggested that the TERT rs10069690 polymorphism may be a risk factor for cancer, especially breast cancer, ovarian cancer, lung cancer, thyroid cancer, and RCC. Further functional studies are warranted to reveal the role of the polymorphism in carcinogenesis.

Evaluation of GALNT16 polymorphisms to breast cancer risk in Chinese population.

BACKGROUND: Polypeptide N-acetylgalactosaminyltransferase 16 (GALNT16) is an N-acetylgalactosaminyltransferase gene that alters protein O-glycosylation, which plays a role in tumor development. This study aims to explore the association of eight GALNT16 polymorphisms with susceptibility to breast cancer (BC). METHODS: This case-control study included 563 BC patients and 552 age-matched healthy controls from the Chinese Han population. The genotypes of GALNT16 polymorphisms were detected using the Agena MassARRAY. The relationship between GALNT16 polymorphisms and BC risk was evaluated using a chi-squared test with an odds ratio (OR) and 95% confidence intervals (CI) under five genetic models. RESULTS: We observed that rs2105269 and rs72625676 were associated with higher BC risk in younger patients with age ≤51 (rs2105269, codominant: p = .006; recessive: p = .005 additive: p = .018; and allele: p = .012; rs72625676, codominant: p = .038; recessive: p = .037). For rs1275678 polymorphism, there was a significantly decreased risk of BC among elder patients (codominant: p = .017; dominant: p = .019; additive: p = .030; and allele: p = .029). Further analysis by clinical characteristics showed rs2105269 was associated with tumor size and lymph node metastasis. CONCLUSION: Our study suggests that GALNT16 polymorphisms are associated with BC susceptibility in Chinese population.

Analysis of MIR155HG variants and colorectal cancer susceptibility in Han Chinese population.

BACKGROUND: MIR155HG plays an important role in malignant tumors, but it is rarely reported in the occurrence and development of colorectal cancer (CRC). This study investigated the effects of MIR155HG polymorphisms on CRC susceptibility from the perspective of molecular genetics. METHODS: Eight SNPs in MIR155HG were selected and genotyped among 514 CRC cases and 510 healthy controls using the Agena MassARRAY platform. The associations between these SNPs and the CRC risk were evaluated under genetic models using conditional logistic regression analysis. The HaploReg v4.1 database was used for SNPs functional prediction. RESULTS: The allele "C" of rs12482371 (p = 0.047), allele "C" of rs1893650 (p = 0.025), and the allele "A" of rs928883 (p = 0.037) in MIR155HG were significantly associated with CRC risk. Genetic model analysis revealed that rs12482371 and rs1893650 increased CRC risk; whereas rs928883 was associated with reduced CRC risk. Stratification analysis showed that rs9383938 was a protective factor in CRC patients under 60 years old. Rs12482371 and rs1893650 were associated with the CRC risk in females. Rs11911469 and rs34904192 may affect the clinical stage and lymph node metastasis. Moreover, the haplotypes CTT and GTC of LD block rs4143370|rs77218221|rs12482371, and the haplotypes CATGA and CACGG of LD block rs77699734|rs11911469|rs1893650|rs34904192|rs928883 were significantly associated with CRC risk. CONCLUSION: This study revealed that MIR155HG SNPs were associated with CRC susceptibility and could be predictive biomarkers for CRC risk.

Expression of miR-103a-3p in breast cancer tissues and its suppression on glycolysis and proliferation of breast cancer cells via down-regulating PDK4 / 中国肿瘤生物治疗杂志

@#[Abstract] Objective： ： To explore miR-103a-3p expression in the tumor tissues and the serum of breast cancer patients, and its role and mechanism in breast cancer development. Methods: Pathologically confirmed 31 cases of tumor tissues and 21 cases of para-cancerous tissues resected at Department of Oncological Surgery of the Second Affiliated Hospital of Hainan Medical University (Haikou, China) from March 1, 2017 to August 31，2017 were collected for this study; in addition, serum samples from 38 breast cancer patients and 22 healthy subjects as well as the breast cancer cell lines MCF-7 and MDA-MB-231 were used in this study. pHBLV-U6-Luc-T2A-Puro and PLL3.7 lentivirus were applied to knock down miR-103a-3p and PDK4 in MCF-7 and MDA-MB-231 cells, respectively. qPCR and Western blotting were performed to examine the mRNA and protein expressions of miR-103a-3p and PDK4 in tissues and serums of breast cancer patients as well as the in cell lines, respectively; CCK-8 assay was applied to detect the proliferation of MCF-7 and MDAMB-231 cells; Olympus AU5400 was applied to detect the glucose consumption and lactate production in indicated cell line. Results： ： miR-103a-3p was significantly decreased in tumor tissues compared with the paracancerous tissues (P<0.01). miR-103a-3p knockdown activated the glucos consumption and lactate production (all P<0.01), increased the PKD4 expression (P<0.01) in MCF-7 and MDAMD-231 cells, and promoted the proliferation of MCF-7 and MDA-MB-231 cells (P<0.01). Furthermore, knockdown of PDK4 suppressed the glucose consumption, lactate production and proliferation in MCF-7 and MDA-MB-231 cells with miR-103a-3p silencing (all P<0.01). Conclusion： ：In the breast cancer, miR-103a-3p inhibited the proliferation of breast cancer cells through down-regulation of PDK4 and PDK4-mediated aerobic glycolysis.

Simultaneous breast reconstruction and treatment of breast cancer-related upper arm lymphedema with lymphatic lower abdominal flap.

BACKGROUND: This study was designed to introduce the key points about the transplantation of lower abdominal flap with vascularized lymph node and to evaluate the effect of breast restoration, breast reconstruction, and lymphatic transplantation to treat upper limb lymphedema after breast cancer surgery. MATERIALS AND METHODS: The study was based on the retrospective study on 10 cases of postmastectomy lymphedema during January 2008 to March 2011. All patients, aged 36 to 50 years, have had one-side upper-limb lymphedema for 3 to 5 years. Six patients had accepted radiotherapy. Four patients had a diagnosis of severe lymphedema, and 2 patients had moderate lymphedema. The isotope radiography before the operation showed obstruction of lymphatic return, and the multidetector computed tomography that followed delivered a clear picture of the abdominal flap blood supply and the blood vessels in the breasts. During the operation, the scar contracture of the axilla was completely relaxed, and all patients accepted abdominal transplantation of lower abdominal flap with vascularized lymph node. After the operation, the elastic bandages were applied for one year as an adjuvant therapy. The follow-up visits were conducted 1, 3, 6, and 12 months after the surgery. The measurement indexes included mid-upper arm circumference, clinical symptoms, and lymphoscintigraphy. RESULTS: All flaps worked well. One patient was found to have delayed wound healing; one patient saw no obvious improvement in lymphedema; 7 patients with lymphedema were relieved with apparent improvement in the affected limbs' mean perimeter and clinical symptoms; one patient recovered; and another patient was lost to follow-up. The mean reduction was 2.122±2.331 cm, and the reduction of the lymphedematous limb was statistically significant between the preoperative and 12-month postoperative groups (P<0.05). The results were good in 4 patients and excellent in one patient. CONCLUSIONS: The transplantation of abdominal flap with vascularized lymph node and breast reconstruction, accompanied by the treatment to upper limb lymphedema and using elastic bandages as an adjuvant therapy, is considered to be an effective method to restore the configuration and function of breasts. Long-term follow-up visits are undergoing, especially the lymphoscintigraphy, 2 years after the operation.