Therapeutic Potential of Melatonin in the Regulation of MiR-148a-3p and Angiogenic Factors in Breast Cancer

Abstract

Background: The high mortality rate of breast cancer is related to the occurrence of metastasis, a process that is promoted by tumor angiogenesis. MicroRNAs are small molecules of noncoding mRNA that play a key role in gene regulation and are directly involved in the progression and angiogenesis of various tumor types, including breast cancer. Several miRNAs have been described as promoters or suppressors angiogenesis and may be associated with tumor growth and metastasis. Melatonin is an oncostatic agent with a capacity of modifying the expression of innumerable genes and miRNAs related to cancer. Objective: The aim of this study was to evaluate the role of melatonin and the tumor suppressor miR- 148a-3p on angiogenesis of breast cancer. Method: MDA-MB-231 cells were treated with melatonin and modified with the overexpression of miR-148a-3p. The relative quantification in real-time of miR-148a-3p, IGF-IR and VEGF was performed by real-time PCR. The protein expression of these targets was performed by immunocytochemistry and immunohistochemistry. Survival, migration and invasion rates of tumor cells were evaluated. Finally, the xenograft model of breast cancer was performed to confirm the role of melatonin in the tumor. Results: The melatonin was able to increase the gene level of miR-148a-3p and decreased the gene and protein expression of IGF-1R and VEGF, both in vitro and in vivo. In addition, it also had an inhibitory effect on the survival, migration and invasion of breast tumor cells. Conclusion: Our results confirm the role of melatonin in the regulation of miR-148a-3p and decrease of angiogenic factors.

Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H+-Centered Anticancer Paradigm of the Late Post-Warburg Era

“…MT plays a number of other different actions as an anti-cancer agent [ 283 ]. Among them, it regulates the expression of estrogen receptors (ER), inhibits enzymes involved in the local synthesis of estrogens, activates the immune system and decreases angiogenesis by downregulating VEGF [ 280 , 284 , 285 , 286 ]. Finally, MT also inhibits other different angiogenic factors under hypoxic conditions [ 286 ].…”

A New and Integral Approach to the Etiopathogenesis and Treatment of Breast Cancer based upon its Hydrogen Ion Dynamics

“…Sonehara et al, have shown that treatment with MT modulates tumor aggressiveness, increasing apoptosis under microenvironmental acidosis in BC cell lines [222]. Importantly, MT has shown to be a significant antiangiogenic agent by downregulating VEGF expression in human BC cells [216,223]. Previous studies have also indicated that MT suppresses tumor aerobic metabolism (Warburg effect) and…”

“…In summary, it is beyond doubt that MT plays an important role in the prevention and treatment of BC. Although its primary effect seems to be exerted at a mitochondrial level by regulating aerobic metabolism, MT also decreases angiogenesis and proliferation while promoting apoptosis [216,217,222,223,226].…”

A meta‐analysis of microRNA networks regulated by melatonin in cancer: Portrait of potential candidates for breast cancer treatment

“…We initially performed a systematic meta-analysis to identify miRNA expression profiles targeted by melatonin in experimentally relevant studies. Based on the design criteria for eligibility ( Figure 1), 14 studies [47][48][49][50][51][52][53][54][55][56][57][58][59][60] were selected to investigate the miRNAs expression changes induced by melatonin treatment (Table S1). Among the 46 differentially expressed miRNAs, 29 were upregulated, and 17 were downregulated (Table S2).…”