Circ_0001756, a novel biomarker, promotes breast cancer progression via miR-584-5p/TRAF6 signaling axis
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Abstract Purpose Circular RNAs (circRNAs) appear to exert critical functions in breast cancer (BC). The objective of this study is to explore the usefulness of circRNAs as potential diagnostic and prognostic biomarkers of BC. Methods The Gene Expression Omnibus database was referenced to identify differentially expressed circRNAs in BC. We found that circ_0001756 was associated with the malignant potential of BC. Also, the expression levels of circ_0001756 in BC tissues and cell lines were determined by real-time quantitative polymerase chain reaction analysis. The functions of circ_0001756 were investigated both in vitro and in vivo . The luciferase reporter and rescue assays were used to clarify the molecular mechanisms of circ_0001756. Additionally, the clinical value of circ_0001756 as a serum biomarker and potential correlations with the clinicopathological characteristics of BC patients were investigated. Results Circ_0001756 expression was upregulated in BC tissues and substantially correlated with tumor size and tumor-node-metastasis (TNM) stage. Knockdown of circ_0001756 markedly inhibited the malignant potential of BC both in vitro and in vivo . Mechanistically, circ_0001756 acted as a miR-584-5p sponge to regulate TRAF6 in BC cells. Serum levels of circ_0001756 were significantly higher in pre-operative BC patients than in healthy controls, fibroadenoma patients, and post-operative BC patients. Also, serum circ_0001756 was remarkably correlated with tumor size, patient age, metastasis state, and TNM stage. The combination of the traditional tumor markers carcinoembryonic antigen and cancer antigen 15 − 3 with circ_0001756 significantly improved the diagnostic accuracy of BC. Conclusion Circ_0001756 promotes the malignancy of BC through the miR-584-5p/TRAF6 signaling axis. Additionally, serum circ_0001756 is a promising biomarker for screening and diagnosis of BC.Keywords:
Carcinoembryonic antigen
Carcinoembryonic antigen has been used to monitor colorectal cancer treated patients, elevated carcinoembryonic antigen allows to predict recurrence however some serum levels is not ever a sign of disease. In a last paper 21% of the colorectal cancer patients treated surgically had not recurrent disease. The aim of the study was to follow these patients for at least one year. Thirty two patients with elevated carcinoembryonic antigen serum levels were studied. Five were excluded and 27 were followed with chest RX, computadorized tomography and colonoscopy. Carcinoembryonic antigen serum levels were measured by ELISA using Sorine Biomedica kit (normal value: 5 ng/ml). Eleven patients (41%) developed recurrence, seven had liver metastasis. The mean time among the elevated serum carcinoembryonic antigen and the recurrence was 6.6 months. The recurrence was not observed in 18 patients, the carcinoembryonic antigen serum levels become normal in eight and in the eight others the carcinoembryonic antigen serum levels persisted elevated. Carcinoembryonic antigen serum levels can be elevated before the diagnosis of recurrence, mostly in liver metastasis, however, a number of patients with elevated carcinoembryonic antigen serum levels do not have a known cause.
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Carcinoembryonic antigen rarely exceeds serum levels of 10-12 ng/mL in benign diseases and has never been found above 24 ng/ml. We report a case in which carcinoembryonic antigen serum levels reached the value of 44.9 ng/ml without any overt reason (after 22 months of follow-up). A decline of the carcinoembryonic antigen to normal ranges was noticed after a radiolabeled anti-carcinoembryonic antigen monoclonal antibody scan was performed. The reason for this phenomenon is unclear.
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Serum carcinoembryonic antigen is used mainly for tumor follow-up to detect recurrence of colonic cancer. However, raised preoperative carcinoembryonic antigen levels may be helpful for the identification of understaged cases and of patients meriting more intensive preoperative and postoperative diagnostic workup.From a prospectively collected database, the data on 261 patients who had curative colonic carcinoma with a minimal follow-up of five years and who had preoperative carcinoembryonic antigen levels assessed were retrieved and analyzed. Outcome parameters were local and/or distant recurrence and time to recurrence. These parameters were correlated with Dukes staging and preoperative carcinoembryonic antigen levels.The cumulative disease-free survival of patients with a preoperative carcinoembryonic antigen level within the normal range was significantly better than that of those whose carcinoembryonic antigen was 5 ng/ml or more (P = 0.001). No patient with carcinoembryonic antigen levels less than 1 ng/ml developed metastatic recurrence. Twenty-three percent of all patients with a raised carcinoembryonic antigen above 5 ng/ml compared with 2.1 percent of patients with carcinoembryonic antigen below 5 ng/ml developed a metastasis at two years. At five years, these figures were 37.2 percent and 7.5 percent, respectively. Dukes staging and carcinoembryonic antigen levels were found to be directly correlated (P < 0.001) when all patients were included. Carcinoembryonic antigen of more of 15 ng/ml was found to be a significant adverse prognostic indicator for disease-free survival irrespective of Dukes staging (P < 0.02). Raised carcinoembryonic antigen levels predicted distant metastatic recurrence (P < 0.001) but did not predict local recurrence (P = 0.72).High preoperative carcinoembryonic antigen levels above 15 ng/ml predicted an increased risk of metastatic recurrence in potentially curative colonic cancer and may indicate undetectable disseminated disease. Preoperative carcinoembryonic antigen levels predict understaging and the possibility of distant recurrence. Such patients may therefore be selected for adjuvant therapy where indicated. Therefore, carcinoembryonic antigen is complementary to conventional Dukes staging for the prediction of recurrence and survival.
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Carcinoembryonic antigen
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Since it has been suggested that colonic obstruction due to carcinoma may play a role in elevations of circulating carcinoembryonic antigen, serial plasma carcinoembryonic antigen levels were studies in 19 patients with intestinal obstruction due to tumor and nontumor causes. Regardless of cause, eight of ten patients with colonic obstruction did not show decreased carcinoembryonic antigen levels after decompression. Two patients with postoperative carcinoembryonic antigen reductions of greater than 40 per cent had ascite removed at operation. Removal of a large volume of carcinoembryonic antigen-rich ascites was thought to contribute to the fall in circulating carcinoembryonic antigen. Six patients with small intestinal obstruction and one patient with large and small intestinal obstruction did not show a reduction in postdecompression carcinoembryonic antigen levels. One patient with Crohn's disease who underwent ileal resection and one with intestinal obstruction due to carcinoma of the ovary who underwent resection at the time of decompression had a greater than 40 per cent reduction in postoperative carcinoembryonic antigen levels. Inflamed intestinal and carcinoma of the ovary are known sources of carcinoembryonic antigen and their removal could explain the decrease in carcinoembryonic antigen. Rehydration, as monitored by plasma osmolality and protein concentration, did not explain changes in plasma carcinoembryonic antigen. Thus, it appears that carcinoembryonic antigen production may play a more significant role in the regulation of circulating carcinoembryonic antigen than the physiopathologic processes associated with obstruction.
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The aim of this study was to evaluate the serum carcinoembryonic antigen levels in the diagnosis and in monitoring colorectal cancer patients at different Dukes' stage. Carcinoembryonic antigen serum levels were measured by Elisa using Sorine Biomedica kit (normal value: 5 ng/ml) in 240 colorectal adenocarcinoma. In the diagnosis, carcinoembryonic antigen levels were measured in 109 patients, in 42% of them, the carcinoembryonic antigen levels were elevated. The carcinoembryonic antigen levels were also evaluated in 309 serum from treated colorectal cancer patients. Fifty-nine percent of the serum of the patients with recurrence disease had elevated carcinoembryonic antigen levels and 41% of the serum of patients without recurrence also have elevated serum carcinoembryonic antigen levels. Ninety percent of the serum from treated patients without recurrence have normal serum carcinoembryonic antigen levels. We concluded that the sensitivity of carcinoembryonic antigen is lower in the diagnosis as described in others studies, mostly in patients with better prognosis. In the monitoring, patients with normal serum carcinoembryonic antigen levels, probably have no recurrence of the disease. In the other hand, patients with elevated serum carcinoembryonic antigen levels can have or not relapsed disease.
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The CEA-plasma level was determined in 10 patients with malignant obstruction of the large intestine and in 6 patients with benign obstruction of the small intestine. The plasma carcinoembryonic antigen levels were obtained prior to initiating of the treatment and sequentially after treating the complete obstruction. Elevated plasma carcinoembryonic antigen levels are related to the carcinoembryonic antigen production by the primary tumour and not additionally to the obstruction. An elevated plasma CEA level in patients with benign obstruction could not be detected. After relief of obstruction, significant changes in the mean carcinoembryonic antigen values could not be observed.
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Our patients have demonstrated that serial carcinoembryonic antigen determinations contributed to the detection of recurrent tumor and that shortening the delay between carcinoembryonic antigen elevation and reoperation has resulted in an increase from 27 to 78 per cent in instances of resectable recurrent tumor encountered. If these results continue to be substantiated, the carcinoembryonic antigen assay has made a significant contribution in the control of this disease. Serial carcinoembryonic antigen assays should be performed every two months. All benign inflammatory conditions that cause carcinoembryonic antigen elevations must be searched for, and ruled out, before reoperation is decided upon. The physician must be cognizant not only of the significance of the assay but also of the limitations, and he must rely heavily on his clinical judgment.
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A radioimmunoassay for carcinoembryonic antigen with utilization of the so-called sandwich method was established and used for clinical investigation. A collaborative study was made through the cooperation of 34 institutions in Japan, and serum samples from about 400 normal adults, 500 patients with benign diseases, and 1500 cancer patients were assayed. About 90% of the normal adults showed carcinoembryonic antigen levels of under 2.5 ng/ml. The benign disease group showed somewhat higher levels than did the normal group, and the cancer group had levels significantly higher than those of the benign group. The levels were strikingly high in cases of advanced cancer with metastases. The specificity of carcinoembryonic antigen and its antiserum is discussed.
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We recently developed a piggyback knockdown method that was used to knockdown genes in adult zebrafish. In this method, a vivo morpholino (VMO) piggybacks an antisense deoxyoligonucleotide (dO) into the somatic cells and reduces the cognate mRNA levels. In this paper, we tested whether we can piggyback more than one dO with one VMO. We designed various hybrids that had more than one dO that could be piggybacked with one VMO. We chose f7, f8, and αIIb genes and tested their knockdown by the appropriate assays. The knockdown with piggybacking either two or three dOs by one VMO yielded > 85% knockdown efficiency. We also performed knockdown of argonautes and rnaseh separately along with f7. We found the knockdown of f7 occurs when knockdown of argonautes happens and not when rnaseh knockdown was performed, suggesting that RNaseH is involved in mRNA degradation. In conclusion, we developed a method where we could knockdown three genes at one time, and by increasing the concentration of VMO by twofold, we could knockdown six genes simultaneously. These multiple gene knockdowns will not only increase the efficiency of the method in whole genome-wide knockdowns but will also be useful to study multifactorial disorders.
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