To the best of our knowledge, there is not much literature available on studies of miRNAs carried out in umbilical cord tissue. Several studies have conducted analyses of miRNAs in umbilical cord blood or plasma(28–30), or even using newborn screening cards(30). Mas-Parés et al(31). assessed the profiles of miRNAs in umbilical cord tissue in SGA and AGA neonates, and their subsequent association with postnatal catch-up growth. But our study is the first to analyze the microRNA profile in umbilical cord tissue, comparing three different birth weight groups: SGA, AGA and LGA.
Taking into account our results, the most significant differences were found in the expression of the following miRNAs: compared with AGA and LGA, miR-324-3p was downregulated in SGA, miR-337-3p was upregulated in LGA in comparison to both SGA and AGA, miR-760 was downregulated in LGA compared to SGA and AGA, and miR-4707-3p, miR-548a-3p and miR-6733-5p were upregulated in both SGA and LGA in comparison to AGA.
Dysregulation of miR-324 has been described in a variety of tumor types and cancer cell lines(32). Most of studies have stated downregulation of miR-324 in these samples. Regarding non-malignant conditions, miR-324-3p has been reported as an inducer of proinflammatory transcription factor nuclear factor-kB and was related to inflammation and cell death in the central nervous system(33). In the same line of research, other authors have observed that target genes of miR-324-3p are involved in the regulation of inflammation and these same researchers found a strong correlation between the decrease of this miRNA and obesity in young women(34). Carreras-Badosa and cols.(35) conducted a study to assess the circulating miRNA pattern in women with gestational and pregestational obesity, and to evaluate its association with prenatal and postnatal growth markers. They observed that a decrease in miR-324-3p in maternal blood was associated with both gestational and pregestational obesity, while its increase was related to lower weight gain during pregnancy.
Our findings are inconsistent with these data reported in the literature, as our study has revealed a downregulation in miR-324-3p in SGA children compared to both AGA and LGA, showing significant differences. However, the study by Rodosthenous et al.(36) aimed to establish the association between miRNAs and fetal growth alterations by comparing the blood of mothers with SGA neonates, mothers with LGA infants, and mothers with AGA newborns. They found that decreased levels of miR-324-3p in maternal blood were associated with lower gestational age, which supports our findings. Nevertheless, our findings differ in that they occur in umbilical cord tissue, whereas those of the described study were analyzed in maternal blood. These researchers also found that mothers with elevated levels of miR-324-3p had a lower risk of giving birth to SGA neonates compared to AGA.
Regarding the miR-337-3p molecule, it has also been associated with various types of tumors. Furthermore, in several studies, its association has been observed with fat metabolism, fatty acids, and insulin resistance. In our data we found that miR-337-3p was upregulated in LGA in comparison to SGA and AGA. In the study by Vonhogen et al.(37), they discovered that miR-337-3p suppresses the target TWIST1, which acts as a negative regulator of brown fat metabolism, thereby enhances the browning of adipocytes. These findings are in line with our data, as we observed an increase in this miRNA in LGA neonates. Additionally, due to being neonates, they already exhibit a higher proportion of brown fat than in adults.
Previous studies had found decreased expression of miR-337-3p in embryonic tissue from ectopic pregnancies(38), and other authors also linked it to insulin resistance(39). However, these results have not been subsequently confirmed. A recent study in 2023(40) has found that miR-337-3p could influence various genes involved in glycolipid metabolism, suggesting it could be a novel therapeutic target for metabolic diseases. However, these findings have limited relevance to our results.
As for miR-760, it has been consistently associated with various types of tumorous processes in most publications where it appears. It has been implicated in various types of cancer, such as ovarian, liver and colorectal cancer(41). It has been proposed as a therapeutic target or biomarker for cancer treatment and diagnosis. Outside the oncological field, this microRNA has also been associated with certain neurodegenerative diseases such as spinocerebellar ataxia type 1, due to its involvement in the metabolic pathway of the ATXN1 protein, which is related to the pathophysiology of this disease(42). In our sample, we found a decrease in miR-760 in LGA compared to SGA and AGA. However, we have not found data in the literature to support these results.
Finally, we also found that, upon analyzing our samples, miR-4707-3p, miR-548a-3p, and miR-6733-5p were upregulated in both Small for Gestational Age (SGA) and Large for Gestational Age (LGA) compared to Appropriate for Gestational Age (AGA). That is to say, there was an elevation of these three molecules in newborns with fetal growth alteration, due to either excess or deficiency. However, once again, after conducting an exhaustive literature search on these molecules, it yields very few results, and in any case, they are not related to our study topic. Instead, they associate these molecules with various types of tumors(43–45), rheumatoid arthritis(46), or ophthalmological disorders(47, 48).
Therefore, we have found scarce literature supporting our findings. We attribute this, in part, to the fact that it is a currently underexplored topic with few publications available. Additionally, our results were obtained from samples of umbilical cord tissue, which may differ from those obtained in other types of fluids or tissues. Lastly, we would like to highlight as a limitation of our study that it has been conducted on a limited number of samples, which could introduce bias when analyzing and generalizing these results to the general population. However, we believe further studies in this area are necessary, as the study of miRNAs is a burgeoning field in molecular biology that could have significant implications for both diagnostic and therapeutic purposes in the future.
In conclusion, this exploratory study suggests that the expression of miRNAs in umbilical cord tissue is associated with birth weight. Our findings highlight the downregulation of miRNA-324-3p in newborns with Small for Gestational Age (SGA), leading us to conclude that its decrease could serve as a marker for low birth weight. However, further studies are needed to expand upon this information.