miRNA Changes in Adrenal Glands Implicated in Cushing’s Subtypes
Understanding the pathways in excess cortisol production across subtypes may help develop better treatment options
Certain molecules called microRNAs (miRNAs) that act to regulate protein production could underlie certain Cushing’s syndrome subtypes, a study found.
Better understanding the role of these miRNAs and the proteins they affect will help facilitate a better understanding of disease processes, as well as the development of better treatments for Cushing’s, the researchers noted.
The study, “Characterization of Adrenal miRNA-Based Dysregulations in Cushing’s Syndrome,” was published in the International Journal of Molecular Sciences.
Cushing’s syndrome encompasses a group of disorders marked by excessive cortisol production in the body, but the underlying cause of this excess varies by subtype.
In some cases, Cushing’s is driven by the excessive production of adrenocorticotrophic hormone (ACTH) in the brain’s pituitary gland, which signals the adrenal glands sitting atop the kidneys to produce more cortisol. Other types are independent of ACTH.
Treatment is typically based on the underlying cause. For example, in patients with Cushing’s disease — an ACTH-dependent form of Cushing’s caused by pituitary tumors — the first choice of treatment is tumor removal surgery.
But researchers say a better understanding of the pathways involved in excess cortisol production across Cushing’s subtypes will help develop better treatment options.
Normally, proteins are produced from a DNA template via an intermediate molecule called messenger RNA (mRNA). Small molecules called microRNAs, or miRNAs, also circulate in the body and act to silence mRNA in order to regulate protein production.
In a previous study, researchers identified differences in circulating miRNA levels between between people with Cushing’s disease, the most common ACTH-dependent type of Cushing’s, and patients with cortisol-producing adrenocortical adenomas (CPA) — the most common ACTH-independent type.
They have now evaluated differences in miRNAs in adrenal gland tissues harvested from people with Cushing’s disease, CPA, and healthy participants, who served as controls.
They found the levels of 38 miRNAs were different in CPA patients compared with controls, and 17 miRNAs were different in Cushing’s disease patients compared with controls.
Some miRNAs that showed the greatest alterations across additional Cushing’s subtypes were also evaluated.
One in particular — miR-1247-5p — was increased in both CPA and primary bilateral macronodular adrenocortical hyperplasia (PBMAH), another ACTH-independent type, compared with controls and ACTH-dependent types.
A different molecule, called miR-379-5p, was increased in both Cushing’s disease and PBMAH compared to controls.
In mice injected with ACTH, levels of neither of these two miRNAs were altered, suggesting their altered behavior in Cushing’s is likely independent of ACTH, the researchers noted.
The team then aimed to identify which mRNAs these miRNAs might regulate. Overall, levels of 28 mRNAs predicted to be targets 0f miR-1247-5p were significantly changed in CPA samples. In PBMAH samples, 23 mRNAs predicted to change in response to miR-379-5p were also altered.
Many of the mRNAs in both groups were associated with the WNT pathway — a signaling cascade involved in a range of developmental processes. According to researchers, impairments in WNT signaling have been identified in both CPA and Cushing’s disease.
“Thus, it could be hypothesized that by targeting specific genes in the pathway, miRNAs drive specific pathophysiological [disease-related] processes in diverse [Cushing’s syndrome] subtypes,” the researchers wrote.
Two particular mRNAs in the WNT pathway — DVL1 and ROR1 — were increased in CPA and PBMAH samples, respectively, compared with controls. Given the typical role of miRNAs in suppressing mRNA levels, this finding is surprising and warrants further investigation, the researchers noted.
Study findings identified distinct miRNAs in the adrenal glands which are associated with particular Cushing’s subtypes.
Researchers noted that their experiments served to identify miRNAs and mRNA targets that could be involved in specific Cushing’s subtypes, but added that “extensive mechanistic analyses based on these potential targets” will help to better understand their role.