Abstract Background Approximately 25% of patients with early-stage breast cancer experience cancer progression throughout the disease course. Alterations in TMEM240 in breast cancer were identified and investigated to monitor treatment response and disease progression. Methods Circulating methylated TMEM240 in the plasma of breast cancer patients was used to monitor treatment response and disease progression. The Cancer Genome Atlas (TCGA) data in Western countries and Illumina methylation arrays in Taiwanese breast cancer patients were used to identify novel hypermethylated CpG sites and genes related to poor hormone therapy response. Quantitative methylation-specific PCR (QMSP), real-time reverse transcription PCR, and immunohistochemical analyses were performed to measure DNA methylation and mRNA and protein expression levels in 394 samples from Taiwanese and Korean breast cancer patients. TMEM240 gene manipulation, viability, migration assays, RNA-seq, and MetaCore were performed to determine its biological functions and relationship to hormone drug treatment response in breast cancer cells. Results Aberrant methylated TMEM240 was identified in breast cancer patients with poor hormone therapy response using genome-wide methylation analysis in the Taiwan and TCGA breast cancer cohorts. A cell model showed that TMEM240, which is localized to the cell membrane and cytoplasm, represses breast cancer cell proliferation and migration and regulates the expression levels of enzymes involved in estrone and estradiol metabolism. TMEM240 protein expression was observed in normal breast tissues but was not detected in 88.2% (67/76) of breast tumors and in 90.0% (9/10) of metastatic tumors from breast cancer patients. QMSP revealed that in 54.5% (55/101) of Taiwanese breast cancer patients, the methylation level of TMEM240 was at least twofold higher in tumor tissues than in matched normal breast tissues. Patients with hypermethylation of TMEM240 had poor 10-year overall survival ( p = 0.003) and poor treatment response, especially hormone therapy response ( p < 0.001). Circulating methylated TMEM240 dramatically and gradually decreased and then diminished in patients without disease progression, whereas it returned and its levels in plasma rose again in patients with disease progression. Prediction of disease progression based on circulating methylated TMEM240 was found to have 87.5% sensitivity, 93.1% specificity, and 90.2% accuracy. Conclusions Hypermethylation of TMEM240 is a potential biomarker for treatment response and disease progression monitoring in breast cancer.
Androgen deprivation therapy remains the principal treatment for patients with advanced prostate cancer, though, most patients will eventually develop hormone-refractory prostate cancer (HRPC). Androgen ablation mediated maspin-induction has been identified in cancer patients. However, the role of maspin on the anticancer activity of curcumin derived from turmeric (Curcuma longa) in HRPC cells has not been elucidated.The anticancer action of curcumin in hormone-independent prostate cancer cells (DU145, and PC-3) was determined by measures of cell survival rate. The cause of maspin silencing on the anti-tumor abilities of curcumin in PC-3 cells was evaluated by measures of cell survival rate, cell-cycle distribution, and apoptosis signaling analysis.Our present study showed that PC-3 cells (with higher maspin expression) were more sensitive than DU145 cells to curcumin treatment (with lower maspin expression). RNA interference-mediated maspin silencing reduced curcumin sensitivity of PC-3 cells, as evidenced by reduced apoptotic cell death. After exposure to curcumin, maspin-knockdown cells showed lower expression levels of pro-apoptotic proteins, Bad and Bax, as compared with control cells.Maspin can enhance the sensitivity of HRPC cells to curcumin treatment.
Background: Endoscopy-assisted total mastectomy has been used for surgical intervention of breast cancer patients; however, large cohort studies with long-term follow-up data are lacking. Methods: Breast cancer patients who underwent endoscopy-assisted total mastectomy from May of 2009 to March of 2018 were collected prospectively from multiple centers. Clinical outcome, impact of different phases, oncologic results, and patient-reported aesthetic outcomes of endoscopy-assisted total mastectomy were reported. Results: A total of 436 endoscopy-assisted total mastectomy procedures were performed; 355 (81.4 percent) were nipple-sparing mastectomy, and 81 (18.6 percent) were skin-sparing mastectomy. Three hundred fourteen (75.4 percent) of the procedures were associated with immediate breast reconstruction; 255 were prosthesis based and 59 were associated with autologous flaps. The positive surgical margin rate for endoscopy-assisted total mastectomy was 2.1 percent. In morbidity evaluation, there were 19 cases (5.4 percent) with partial nipple necrosis, two cases (0.6 percent) with total nipple necrosis, and three cases (0.7 percent) with implant loss. Compared with the early phase, surgeons operating on patients in the middle or late phase had significantly decreased operation time and blood loss. With regard to patient-reported cosmetic outcomes, approximately 94.4 percent were satisfied with the aesthetic results. Patients who underwent breast reconstruction with preservation of the nipple had higher satisfaction rates. Over a median follow-up of 54.1 ± 22.4 months, there were 14 cases of locoregional recurrence (3.2 percent), three distant metastases (0.7 percent), and one mortality (0.2 percent). Conclusion: This multicenter study showed that endoscopy-assisted total mastectomy is a reliable surgical intervention for early breast cancer, with high patient satisfaction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.
MicroRNAs (miRNAs) play an essential role in regulating gene expression in normal and malignant cells. Expression of the microRNA-200 (miR-200) family has been correlated with malignancy in cancers. However, whether miR-200a/b plays a role in curcumin-mediated treatment of hepatocellular carcinoma (HCC) is unknown. We performed miRNA array analyses in two different HCC cell lines (HepG2 and HepJ5). The expression patterns of miR-200 family members were assessed with real-time PCR. We overexpressed miR-200 family members using a lentiviral system and selected stably transduced clones with antibiotics. The anticancer effects of curcumin on J5-200a, J5-200b, and J5-control cells were assessed by MTT assay, flow cytometry cell cycle analysis, and TUNEL assay. We found that HepG2 cells, which were more resistant to curcumin treatment than HepJ5 cells, expressed higher levels of miR-200a/b. The MTT assay revealed that the overexpression of miR-200a/b in HepJ5 cells conferred enhanced resistance to curcumin treatment compared with the control cells. By cell cycle analysis and TUNEL assay, we found that apoptosis was increased dramatically in J5-control cells compared with J5-200a and J5-200b cells after curcumin treatment. Finally, we evaluated the levels of Bcl-2, Bax, and Bad, and found a decrease of Bcl-2 levels and increase of Bad levels in the J5-control cells treated with curcumin. The expression levels of miR-200a/b might determine the therapeutic efficacy of curcumin on HCC cells.
Abstract Background Gene silencing by aberrant DNA methylation of promoter regions remains the most dominant phenomenon occurring during tumorigenesis. Improving the early diagnosis, prognosis, and recurrence prediction of colorectal cancer using noninvasive aberrant DNA methylation biomarkers has encouraging potential. The aim of this study is to characterize the DNA methylation of the promoter region of TMEM240 , as well as gene expression and its effect on cell biological functions and its applications in early detection and outcome prediction. Results Highly methylated CpG sites were identified in the TMEM240 gene by Illumina methylation 450K arrays in 26 Taiwanese patient paired samples and 38 paired samples from The Cancer Genome Atlas (TCGA) colorectal cancer dataset. Transient transfection and knockdown of TMEM240 were performed to demonstrate the role of TMEM240 in colorectal cancer cells. The data showed that TMEM240 could lead to G1 cell cycle arrest, repress cancer cell proliferation, and inhibit cancer cell migration. The quantitative methylation-specific real-time polymerase chain reaction (PCR) results revealed that 87.8% (480 of 547) of the colorectal cancer tumors had hypermethylated TMEM240 , and this was also found in benign tubular adenomas (55.6%). Circulating cell-free methylated TMEM240 was detected in 13 of 25 (52.0%) Taiwanese colorectal cancer patients but in fewer (28.6%) healthy controls. In 72.0% (85/118) of tissue samples, TMEM240 mRNA expression was lower in Taiwanese CRC tumor tissues than in normal colorectal tissues according to real-time reverse transcription PCR results, and this was also found in benign tubular adenomas (44.4%). The TMEM240 protein was analyzed in South Korean and Chinese CRC patient samples using immunohistochemistry. The results exhibited low protein expression in 91.7% (100/109) of tumors and 75.0% (24/32) of metastatic tumors but exhibited high expression in 75.0% (6/8) of normal colon tissues. Multivariate Cox proportional hazards regression analysis found that mRNA expression of TMEM240 was significantly associated with overall, cancer-specific, and recurrence-free survival ( p = 0.012, 0.007, and 0.022, respectively). Conclusions Alterations in TMEM240 are commonly found in Western and Asian populations and can potentially be used for early prediction and as poor prognosis and early-recurrence biomarkers in colorectal cancer.
Following the publication of the above systematic review and meta‑analysis, an interested reader drew to the Editor's attention that there were potentially a number of concerns associated with the eight source papers on which the study had been based. Two of the studies were considered to have been based on 50 Hz electromagnetic fields and not on radiofrequency radiation; furthermore, one reference used an inaccurate risk estimate for the wrong exposure (shiftwork instead of RF), and one of the studies was focused on male breast cancer (the others all being concerned with female breast cancer). These issues were drawn to the attention of the authors, who did prepare a rebuttal in response to the reader's comments. Independently, the Editorial Board also conducted an independent investigation of the reader's claims, and reached the conclusion that the sheer number of corrections that would have been potentially required meant that it would not have been readily feasible to publish a Corrigendum. Taking all the factors into consideration, the Editor of Experimental and Therapeutic Medicine has therefore decided that the article should be retracted from the Journal on account of the number of uncertainties associated with both the way in which the meta‑analysis had been performed and the source papers selected for the study. Note that the authors were not in agreement with the retraction of this paper. The Editor apologizes to the readership of the Journal for any inconvenience caused by the retraction of this article. [the original article was published in Experimental and Therapeutic Medicine 21: 23, 2018; DOI: 10.3892/etm.2020.9455]
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