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Post-operative serum levels of miR-483-5p in ACC patients. (A) Comparison of miR-483-5p levels in NR3yrs (n = 11) and R < 3yrs groups (n = 13). Cycle threshold (Ct) values were converted to absolute number of copies/mL using a dilution series of a known input quantity of synthetic target miRNA run simultaneously with the experimental samples. Statistically significant difference was assessed using Mann–Whitney test (p = 0.0025). Black circles and triangles: patients who received mitotane adjuvant therapy after serum sampling. White circles in the NR3yrs group: Patients 5 and 8 received mitotane adjuvant therapy 0.9 and 1.8 months before serum sampling, respectively. Red symbols: patients with no mitotane therapy throughout their follow-up. (B) Comparison of miR-483-5p levels in NR3yrs and R < 3yrs patients in function of ENSAT stage (stage I: n = 2; stage II: n = 12; stage III: n = 10); ns: non-significant. The lines within the scatter plot represent the mean ± S.E.M of miRNA copy number/mL.
Source publication
We have previously identified serum miR-483-5p as a preoperative diagnosis and prognosis biomarker for adrenocortical cancer (ACC). Here, we aimed to determine whether circulating miR-483-5p levels measured 3 months post-operatively distinguished patients with good prognosis (no recurrence for at least 3 years; NR3yrs) from patients with poor progn...
Citations
... In adrenocortical carcinomas or adrenocorticalomas, miRNAs are used as non-invasive molecular markers for prognostic evaluation within a very short time after surgery. It has been shown in 13 that microRNA-483-5p is significantly more abundant in the serum of patients who have recurred within 3 years after surgery compared to those who have not recurred. Some researchers have found that a specific microRNA can act as an oncogene in some types of cancer while the same microRNA can also act as a cancer cell suppressor in other cancers. ...
Understand the dynamics of cancer stem cells (CSCs), prevent the non-recurrence of cancers and develop therapeutic strategies to destroy both cancer cells and CSCs remain a challenge topic. In this paper, we study both analytically and numerically the dynamics of CSCs under radiotherapy effects. The dynamical model takes into account the diffusion of cells, the de-differentiation (or plasticity) mechanism of differentiated cancer cells (DCs) and the time delay on the interaction between microRNAs molecules (microRNAs) with DCs. The stability of the model system is studied by using a Hopf bifurcation analysis. We mainly investigate on the critical time delay $$\tau _{c}$$ τ c , that represents the time for DCs to transform into CSCs after the interaction of microRNAs with DCs. Using the system parameters, we calculate the value of $$\tau _{c}$$ τ c for prostate, lung and breast cancers. To confirm the analytical predictions, the numerical simulations are performed and show the formation of spatiotemporal circular patterns. Such patterns have been found as promising diagnostic and therapeutic value in management of cancer and various diseases. The radiotherapy is applied in the particular case of prostate model. We calculate the optimum dose of radiation and determine the probability of avoiding local cancer recurrence after radiotherapy treatment. We find numerically a complete eradication of patterns when the radiotherapy is applied before a time $$t < \tau _{c}$$ t < τ c . This scenario induces microRNAs to act as suppressors as experimentally observed in prostate cancer. The results obtained in this paper will provide a better concept for the clinicians and oncologists to understand the complex dynamics of CSCs and to design more efficacious therapeutic strategies to prevent the non-recurrence of cancers.
... It's noteworthy that the dosage of miRNA can lead to varying effects, as evidenced by existing research 38 .Another important investigation is analysis of the patient prognosis associated with miR-483-5p levels. However, it is noteworthy that several studies have already been conducted to assess the prognostic significance of miR-483-5p across various cancer types [56][57][58][59][60][61] . The continuation of this research can provide an insight into prognostic biomarker potential of miR-483-5p. ...
Eukaryotic initiation factor 4E (eIF4E) is a pivotal protein involved in the regulatory mechanism for global protein synthesis in both physiological and pathological conditions. MicroRNAs (miRNAs) play a significant role in regulating gene expression by targeting mRNA. However, the ability of miRNAs to regulate eIF4E and its phosphorylation remains relatively unknown. In this study, we predicted and experimentally verified targets for miR-483-5p, including eukaryotic translation initiation factor eIF4E and its binding proteins, 4E-BPs, that regulate protein synthesis. Using the Web of Science database, we identified 28 experimentally verified miR-483-5p targets, and by the TargetScan database, we found 1818 predicted mRNA targets, including EIF4E, EIF4EBP1, and EIF4EBP2. We verified that miR-483-5p significantly reduced ERK1 and MKNK1 mRNA levels in HEK293 cells. Furthermore, we discovered that miR-483-5p suppressed EIF4EBP1 and EIF4EBP2, but not EIF4E. Finally, we found that miR-483-5p reduced the level of phosphorylated eIF4E (pSer209eIF4E) but not total eIF4E. In conclusion, our study suggests that miR-483-5p's multi-targeting effect on the ERK1/ MKNK1 axis modulates the phosphorylation state of eIF4E. Unlike siRNA, miRNA can have multiple targets in the pathway, and thereby exploring the role of miR-483-5p in various cancer models may uncover therapeutic options.
... Enhanced adrenal cell proliferation clinically translates into a high incidence of adrenal incidentaloma occurring in 2-10% of the population worldwide (1). One third of these patients have mild autonomous cortisol secretion without typical Cushing stigmata but associated with an elevated cardiometabolic morbidity (2)(3)(4). Comparatively, endogenous cortisol excess resulting in Cushing's syndrome (CS) has an incidence of 0.2-5.0 per million people per year (5). In the majority of patients with overt CS, endogenous hypercortisolism is due to adrenocorticotropic hormone (ACTH) secretion by corticotroph adenomas of the pituitary gland resulting in Cushing's disease (CD) (6). ...
Background
We performed a transcriptomic analysis of adrenal signaling pathways in various forms of endogenous Cushing’s syndrome (CS) to define areas of dysregulated and druggable targets.
Methodology
Next-generation sequencing was performed on adrenal samples of patients with primary bilateral macronodular adrenal hyperplasia (PBMAH, n=10) and control adrenal samples (n=8). The validation groups included cortisol-producing adenoma (CPA, n=9) and samples from patients undergoing bilateral adrenalectomy for Cushing’s disease (BADX-CD, n=8). In vivo findings were further characterized using three adrenocortical cell-lines (NCI-H295R, CU-ACC2, MUC1).
Results
Pathway mapping based on significant expression patterns identified PPARG (peroxisome proliferator-activated receptor gamma) pathway as the top hit. Quantitative PCR (QPCR) confirmed that PPARG (l2fc<-1.5) and related genes – FABP4 (l2fc<-5.5), PLIN1 (l2fc<-4.1) and ADIPOQ (l2fc<-3.3) – were significantly downregulated (p<0.005) in PBMAH. Significant downregulation of PPARG was also found in BADX-CD (l2fc<-1.9, p<0.0001) and CPA (l2fc<-1.4, p<0.0001). In vitro studies demonstrated that the PPARG activator rosiglitazone resulted in decreased cell viability in MUC1 and NCI-H295R (p<0.0001). There was also a significant reduction in the production of aldosterone, cortisol, and cortisone in NCI-H295R and in Dihydrotestosterone (DHT) in MUC1 (p<0.05), respectively.
Outcome
This therapeutic effect was independent of the actions of ACTH, postulating a promising application of PPARG activation in endogenous hypercortisolism.
... Furthermore, elevated levels of miR-503, miR-210, and miR-139-5p in the adrenal tissue have been associated with a more aggressive course of PCC (Feinmesser et al. 2015). Data from about 10 studies, 10 in tissues (Faria et al. 2015), 2 in blood samples (Oreglia et al. 2020), and last in blood and tissue samples (Chabre et al. 2013). miRs were investigated as potential prognostic indicators for PCC patients (Table 3). ...
Pheochromocytoma (PCC) is a neuroendocrine tumor that produces and secretes catecholamine from either the adrenal medulla or extra-adrenal locations. MicroRNAs (miRNAs, miR) can be used as biomarkers to detect cancer or the return of a previously treated disease. Blood-borne miRNAs might be envisioned as noninvasive markers of malignancy or prognosis, and new studies demonstrate that microRNAs are released in body fluids as well as tissues. MiRNAs have the potential to be therapeutic targets, which would greatly increase the restricted therapy options for adrenal tumors. This article aims to consolidate and synthesize the most recent studies on miRNAs in PCC, discussing their potential clinical utility as diagnostic and prognostic biomarkers while also addressing their limitations.
... Chabre et al. found that low levels of miR-195 were highly predictive and prognostic of aggressive ACC [171]. In another study on ACC patients, those with lower postoperative miR-483-5p levels had significantly longer recurrence-free and overall survival rates than those with higher miR-483-5p levels [188]. miR-503, miR-1202, and miR-1275 have significant prognostic potential in ACC and are associated with poor survival in ACC patients, as shown in Table 3 [189]. ...
Adrenocortical carcinoma (ACC) is an uncommon aggressive endocrine malignancy that is nonetheless associated with significant mortality and morbidity rates because of endocrine and oncological consequences. Recent genome-wide investigations of ACC have advanced our understanding of the disease, but substantial obstacles remain to overcome regarding diagnosis and prognosis. MicroRNAs (miRNAs, miRs) play a crucial role in the development and metastasis of a wide range of carcinomas by regulating the expression of their target genes through various mechanisms causing translational repression or messenger RNA (mRNA) degradation. Along with miRNAs in the adrenocortical cancerous tissue, circulating miRNAs are considered barely invasive diagnostic or prognostic biomarkers of ACC. miRNAs may serve as treatment targets that expand the rather-limited therapeutic repertoire in the field of ACC. Patients with advanced ACC still have a poor prognosis when using the available treatments, despite a substantial improvement in understanding of the illness over the previous few decades. Accordingly, in this review, we provide a crucial overview of the recent studies in ACC-associated miRNAs regarding their diagnostic, prognostic, and potential therapeutic relevance.
... Thus, our study results demonstrated that miR-483-5p can be used as an independent predictor of VTE in lung cancer patients. Notably, aberrant miR-483-5p has been reported to be a biomarker for other diseases, such as adrenocortical cancer (Oreglia et al., 2020), coronary plaque rupture , and esophageal squamous cell carcinoma (Xue et al., 2017). ...
Background:
Venous thromboembolism (VTE) is a common complication in patients with lung cancer. The important roles of microRNAs (miRNAs) in VTE have emerged, however, studies about the roles of miRNAs in VTE remain scarce. This study aimed to measure the expression of miR-483-5p in lung cancer patients with VTE, evaluate whether miR-483-5p could predict VTE onset in patients, and further evaluate its predictive value in patients with different BMI values.
Methods:
A total of 170 patients with lung cancer were recruited in this study, including 70 patients with VTE, and 110 patients with non-VTE. The expression of miR-483-5p was detected by quantitative real time PCR. Receiver operating characteristic analysis was used to screen VTE patients from non-VTE patients. Whether miR-483-5p was independently associated with VTE onset in lung cancer patients was evaluated by univariate and multivariate logistic regression analyses.
Results:
miR-483-5p was higher in VTE patients than that in non-VTE patients. miR-483-5p was correlated with body mass index (BMI), hypertension, C-reactive protein (CRP), and platelet count in VTE patients. In addition, miR-483-5p had high diagnostic value to differentiate between VTE patients and non-VTE patients and served as an independent biomarker in predicting the VTE onset in lung cancer patients. Moreover, miR-483-5p had the highest diagnostic accuracy to screen VTE patients from non-VTE patients in patients with high BMI values.
Conclusion:
miR-483-5p, increased in VTE patients, can independently predict VTE onset in lung cancer patients especially in patients with high BMI values.
... To date, these patterns have been most helpful in determining prognosis in ACC. The most notable example comes from a retrospective study where miR-483-5p, an miRNA found within an intron of the IGF2 gene was measured in the serum of patients with ACC and found to have 100% specificity for predicting postoperative recurrence within three years [109]. miRNA clusters were also valuable in the TCGA analysis in creating their Cluster of Clusters, which were strongly associated with disease progression rates [19]. ...
Adrenocortical cancer (ACC) typically presents in advanced stages of disease and has a dismal prognosis. One of the foremost reasons for this is the lack of available systemic therapies, with mitotane remaining the backbone of treatment since its discovery in the 1960s, despite underwhelming efficacy. Surgery remains the only potentially curative option, but about half of patients will recur post-operatively, often with metastatic disease. Other local treatment options have been attempted but are only used practically on a case-by-case basis. Over the past few decades there have been significant advances in understanding the molecular background of ACC, but this has not yet translated to better treatment options. Attempts at novel treatment strategies have not provided significant clinical benefit. This paper reviews our current treatment options and molecular understanding of ACC and the reasons why a successful treatment has remained elusive. Additionally, we discuss the knowledge gaps that need to be overcome to bring us closer to successful treatment and ways to bridge them.
... Circulating hsa-miR-483-5p could differentiate recurring and non-recurring ACC. High circulating hsa-miR-483-5p expression was associated with significantly shorter recurrence-free and overall survival [69]. ...
Almost 10 years have passed since the first attempts of liquid biopsy aimed at the characterisation of tumor cells present in the bloodstream from a regular sample of peripheral blood were performed. Liquid biopsy has been used to characterise tumor heterogeneity in various types of solid tumors including adrenocortical carcinoma. The development of molecular biology, genetics, and methodological advances such as digital PCR and next-generation sequencing allowed us to use besides circulating tumor cells a variety of circulating cell-free nucleic acids, DNAs, RNAs and microRNAs secreted by tumors into blood and other body fluids as specific molecular markers. These markers are used for diagnosis, to check tumor development, selecting efficient therapies, therapy monitoring and even possess prognostic power. In adrenocortical carcinoma, there are some studies reporting analysis of circulating tumor cells, circulating cell free DNA and microRNAs for assessing tumor heterogeneity. Among microRNAs, hsa-miR-483-5p seems to be the most important player. Combined with other microRNAs like hsa-miR-195 , their expression correlates with recurrence-free survival. Most studies support the applicability of liquid biopsy for assessing temporal tumor heterogeneity (i.e. tumor progression) in adrenocortical cancer. In this mini-review, the available findings of liquid biopsy for assessing tumor heterogeneity in adrenocortical cancer are presented.
... MiRNAs are found both intratumorally and in circulation. Since circulating miRNAs are easily detectable and highly stable, they are promising diagnostic, prognostic, and therapeutic biomarkers in several tumors, including ACC [23,24,29]. ...
... Chabre et al. [37] investigated circulating miRNA and identified low miR-195 and high miR-483-5p circulating levels as strong predictive/prognostic values for aggressive ACC. In a recent study performed on 48 ACC patients, the same group [29] showed that patients with lower postoperative miR-483-5p levels demonstrated a significant longer recurrence-free and overall survival rate than patients with higher miR-483-5p levels. ...
Non-coding RNAs (ncRNAs) are a type of genetic material that do not encode proteins but regulate the gene expression at an epigenetic level, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The role played by ncRNAs in many physiological and pathological processes has gained attention during the last few decades, as they might be useful in the diagnosis, treatment and management of several human disorders, including endocrine and oncological diseases. Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine cancer, still characterized by high mortality and morbidity due to both endocrine and oncological complications. Despite the rarity of this disease, recently, the role of ncRNA has been quite extensively evaluated in ACC. In order to better explore the role of the ncRNA in human ACC, this review summarizes the current knowledge on ncRNA dysregulation in ACC and its potential role in the diagnosis, treatment, and management of this tumor.
... Chabre et al. has reported for the first time that shorter overall survival was associated with increased miR-483-5p and decreased miR-195 expression in circulation (24). A recent study, measuring miR-483-5p levels three months after surgery, has found that serum miR-483-5p levels were higher in patients with poor prognosis (recurrence or death within 3 years after surgery) than patients with good prognosis (no recurrence for at least 3 years) (48). ...
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with frequent metastatic spread and poor prognosis. The disease can occur at any age with unexpected biological behavior. Recent genome-wide studies of ACC have contributed to our understanding of the disease, but diagnosis of ACC remains a challenge, even for multidisciplinary expert teams. Patients with ACC are frequently diagnosed in advanced stages and have limited therapeutic options. Therefore, for earlier diagnosis and better clinical management of adrenocortical carcinoma, specific, sensitive, and minimal invasive markers are urgently needed. Over several decades, great efforts have been made in discovering novel and reliable diagnostic and prognostic biomarkers including microRNAs, steroid profilings, circulating tumor cells, circulating tumor DNAs and radiomics. In this review, we will summarize these novel noninvasive biomarkers and analyze their values for diagnosis, predicting prognosis, and disease monitoring. Current problems and possible future application of these non-invasive biomarkers will also be discussed.
