MiR-21: an environmental driver of malignant melanoma?

Abstract

Since the mid-1950’s, melanoma incidence has been rising steadily in industrialized Caucasian populations, thereby pointing to the pivotal involvement of environmental factors in melanomagenesis. Recent evidence underlines the crucial role of microRNA (miR) signaling in cancer initiation and progression. Increased miR-21 expression has been observed during the transition from a benign melanocytic lesion to malignant melanoma, exhibiting highest expression of miR-21. Notably, common BRAF and NRAS mutations in cutaneous melanoma are associated with increased miR-21 expression. MiR-21 is an oncomiR that affects critical target genes of malignant melanoma, resulting in sustained proliferation (PTEN, PI3K, Sprouty, PDCD4, FOXO1, TIPE2, p53, cyclin D1), evasion from apoptosis (FOXO1, FBXO11, APAF1, TIMP3, TIPE2), genetic instability (MSH2, FBXO11, hTERT), increased oxidative stress (FOXO1), angiogenesis (PTEN, HIF1α, TIMP3), invasion and metastasis (APAF1, PTEN, PDCD4, TIMP3). The purpose of this review is to provide translational evidence for major environmental and individual factors that increase the risk of melanoma, such as UV irradiation, chemical noxes, air pollution, smoking, chronic inflammation, Western nutrition, obesity, sedentary lifestyle and higher age, which are associated with increased miR-21 signaling. Exosomal miR-21 induced by extrinsic and intrinsic stimuli may be superimposed on mutation-induced miR-21 pathways of melanoma cells. Thus, oncogenic miR-21 signaling may be the converging point of intrinsic and extrinsic stimuli driving melanomagenesis. Future strategies of melanoma treatment and prevention should thus aim at reducing the burden of miR-21 signal transduction.

RETRACTED ARTICLE: Oncogenic transformation of human lung bronchial epithelial cells induced by arsenic involves ROS-dependent activation of STAT3-miR-21-PDCD4 mechanism

“…Increasing evidence indicates that abnormal expression of miRNAs is associated with carcinogenesis45. miR-21 is a key oncogene, plays an important role in the initiation and progression of cancer46 and is highly overexpressed in most cancers474849. miR-21 binds to the 3′-UTR of PDCD4 and suppresses its translation24.…”

Hexavalent chromium induces malignant transformation of human lung bronchial epithelial cells via ROS-dependent activation of miR-21-PDCD4 signaling

“…Significant changes in microRNA (miR) expression in response to environmental exposure in humans have recently been reported [46, 47]. Notably miR-21, a key oncogene, plays an important role in the initiation and progression of cancer [47] and is highly overexpressed in most cancers [48, 49]. miR-21 binds to the 3′-UTR of the tumor suppressor PDCD4 to suppress its translation [4].…”

STAT5 induces miR-21 expression in cutaneous T cell lymphoma

“…Of notice, miR-21 has been implicated in many aspects of cancer pathobiology. For instance, miR-21 promotes genetic instability, sustained proliferation, and apoptosis evasion in cancer cells, enhances angiogenesis, and deregulates cytokine expression by macrophages and stromal cells [60]. Therefore, it is likely that a coordinated up-regulation of miR-21 by malignant and stromal cells act in synergy to promote a tumor permissive micro-environment in CTCL [39].…”