miR-451: A Novel Biomarker and Potential Therapeutic Target for Cancer.

Although great progress has been made in cancer treatments over the past several years, 1 , 2 the overall survival rates for some types of cancers are still very low owing to metastasis, recurrence, and drug resistance. Therefore, the identification of diagnostic molecular biomarkers for early cancer detection and the development of targeted treatments are crucial. Increasing evidence has confirmed that noncoding RNAs (ncRNAs) participate in both physiological and pathological processes, including cell development, differentiation, proliferation, and apoptosis. MicroRNAs (miRNAs or miRs), a subtype of ncRNAs, are a class of small, endogenous, highly conserved, single-stranded noncoding RNAs of approximately 22 nucleotides. 3 They may function as oncogenes or tumor suppressor genes, depending on the cancer type and physiological environment. 4 , 5 More than 2500 mature miRNAs have been identified in the human genome and recorded in the public miRBase database. Among these, more than 1000 regulate over 50% of protein-coding human genes, and each miRNA can control up to 100 gene transcripts. A single miRNA may regulate gene expression at both the transcriptional and posttranscriptional levels by binding to the 3′ untranslated region of hundreds of target messenger RNAs (mRNAs). 6 The identification of downstream target mRNAs is a major focus of miRNA research. Epigenetic and genetic alterations of miRNAs are common events in cancer progression. Therefore, miRNAs have significant promise as diagnostic, prognostic, and therapeutic cancer biomarkers. 7 – 10 miR-451 was first identified in the human pituitary gland in 2005 by Altuvia et al 11 The gene encoding this miRNA is located in human chromosomal region 17qll.2. miR-451 participates in multiple physiological and pathological processes, including hematopoietic system differentiation, 12 embryonic development, epithelial cell polarity, 1 3 ,and nervous system development. 14 It is dysregulated in multiple cancers and participates in numerous cancer-related biological processes, including proliferation, apoptosis, angiogenesis, epithelial-mesenchymal transition (EMT), drug resistance, and metastasis. It often acts as a tumor suppressor gene in cancers and modulates multiple pathways by targeting different downstream mRNAs. In this review, we focus on the function of miR-451 in multiple cancer types and its underlying mechanisms. More importantly, we will discuss the potential of miR-451 as a biomarker for early cancer diagnosis and as a therapeutic candidate for the treatment of metastatic or recurrent cancer and to overcome drug resistance.

The tumor microenvironment includes tumor cells and their adjacent stroma, which mainly contains extracellular matrix components, including fibroblasts, macrophages, cytokines, and signaling molecules. Tumor initiation and progression are complex processes involving consecutive gene mutations and changes in the fundamental biological behavior of cells caused by changes in their neighboring stroma. Recent research has highlighted the significant roles of miRNAs in the interplay between tumor cells and their microenvironments in favor of tumor formation, angiogenesis, metastasis, and resistance to chemo- and radiotherapy. Studies have shown that miR-451 not only directly affects tumor cell proliferation but also indirectly affects tumor cell invasion and metastasis upon secretion into the microenvironment via exosomes. miR-451 is the only reported miRNA that is not processed by Dicer but instead matures via an Ago2-mediated pathway. This unique processing pathway might relate to the high secretion of miR-451. Gu et al 105 reported that the breast microenvironment, including the milk, may contribute to BC initiation and development, as miR-451 was significantly upregulated in the milk of patients with milk stasis plus neoplasm. Khazaei et al 106 evaluated miR-451 expression in esophageal SCC patient serum samples and found that it is mainly secreted into the serum through exosomal compartments. Exosomal miR-451 is overexpressed in the conditioned medium of cocultured KYSE-30 cells and normal fibroblasts, and miR-451-enriched conditioned medium in turn promotes the migration ability of KYSE-30 cells. These data support a signaling role for miR-451 in extracellular matrix cross-talk in the esophageal tumor microenvironment. Surprisingly, miR-451 is also related to cell metabolism and can mediate cell energy-consuming models via several targets. Ansari et al 107 found that miR-451 levels in glioblastoma multiforme cancer cells were high in a glucose-rich environment and low in conditions of glucose depletion, and that miR-451 is a potent inhibitor of the AMPK signaling pathway. Zhao et al 65 demonstrated that miR-451 is downregulated in glioma tissues compared to normal brain tissues, especially in the central portions of tumors, indicating that the microenvironment inside the tumor is heterogeneous. Central glioma cells are in a hypoxic–hypoglycemic microenvironment with low miR-451 expression; therefore, tumor cell growth inhibited and necrosis is apparent. In the peripheral parts of the tumor, the survival of tumor cells is enhanced, and they actively proliferate and infiltrate into the surrounding parenchyma. In glioma cell lines, decreased miR-451 expression suppressed tumor cell proliferation but enhanced migration, concomitant with low level CAB39/AMPK/mTOR pathway activation and strong Rac1/cofilin pathway activation, respectively. Korabecna et al 108 identified five miRNAs derived from cancer cells, including miR-451, that may together regulate 2304 target genes in macrophages, including those involved in cell apoptosis, gene expression, and protein transportation, that may contribute to carcinogenesis. In 2018, Panigrahi et al 2 showed that miR-451 levels were significantly higher in exosomes from human prostate cancer cells under hypoxic conditions than in those under normoxic conditions. These results suggest the potential of miR-451 as a biomarker that influences the tumor microenvironment in patients with prostate cancer.

In this review, we focused on the functions of miR-451 in the progression of multiple cancer types. miR-451 functions as a tumor suppressor and is downregulated in most cancer types. It can be detected in different sample types, such as cancer tissues, blood, saliva, and urine. miR-451 has been associated with multiple target genes and pathways. It functions in both direct and indirect ways. The indirect way via secretion into the tumor microenvironment through exosomes overcomes miRNA degradation by RNase in the serum and endocytic compartments. miR-451 has potential as a biomarker for cancer diagnosis and prognosis or as a treatment target in combination with established drugs to reduce drug resistance. However, its clinical application has a long way to go.