Dr. Jekyll or Mr. Hyde: The multifaceted roles of miR-145-5p in human health and disease

Abstract

MicroRNAs (miRNAs) are classified as small, non-coding RNAs that play crucial roles in diverse biological processes, including cellular development, differentiation, growth, and metabolism. MiRNAs regulate gene expression by recognizing complementary sequences within messenger RNA (mRNA) molecules. Recent studies have revealed that miR-145-5p functions as a tumor suppressor in several cancers, including lung, liver, and breast cancers. Notably, miR-145-5p plays a vital role in the pathophysiology underlying HIV and chronic obstructive pulmonary diseases associated with cigarette smoke. This miRNA is abundant in biofluids and shows potential as a biomarker for the diagnosis and prognosis of several infectious diseases, such as hepatitis B, tuberculosis, and influenza. Additionally, numerous studies have indicated that other non-coding RNAs, including long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), can regulate miR-145-5p. Given the significance of miR-145-5p, a comprehensive overview focusing on its roles in health and disease is essential. This review discusses the dual role of miR-145-5p as a protagonist and antagonist in important human diseases, with particular emphasis on disorders of the respiratory, digestive, nervous, reproductive, endocrine, and urinary systems.

Keywords: Human diseases; Respiratory system; miR-145-5p.

Fig. 1

Role of miR-145-5p in Diverse Pathologies: Insights into Respiratory, Digestive, Nervous, Reproductive, Endocrine, and Urinary Disorders.

Fig. 2

The biogenesis of miRNAs can occur through canonical and noncanonical pathways. In the canonical pathway, primary miRNA (pri-miRNA) transcripts are produced from miRNA genes by RNA Polymerase II or III (RNA pol II/III). These pri-miRNAs are then processed into precursor miRNAs (pre-miRNAs) by the Drosha-DGCR8 complex. In contrast, the noncanonical pathway involves the formation of intronic pre-miRNA hairpins, which are transcribed by RNA Polymerase II. This process includes splicing, debranching, and trimming of short introns (lariat), bypassing the Drosha processing step. The pre-miRNAs generated from both pathways are exported from the nucleus through exportin-5 (Exp 5). Subsequently, Dicer, along with TRBP, processes them into double-stranded RNAs known as mature miRNA duplex. Argonaute (Ago) proteins then unwind these double-stranded RNAs, separating the guide strand (miRNA) from the passenger strand. The mature miRNA is incorporated into the RNA-induced silencing complex [32], which interacts with the 3′ untranslated region (3′ UTR) of target mRNAs to regulate gene expression, primarily through translation inhibition or mRNA degradation.

Fig. 3

The structure of pre-miR-145. Two mature miRNAs, miR-145-5p and miR-145-3p, are generated from the 5′ and 3′ arms of the pre-miR-145 structure.

Fig. 4

Potential roles of miR-145-5p in the development of asthma. This figure has been redrawn from Ref. [85]. A) The expression of miR-145-5p in asthma is associated with the disruption of Wnt/β-catenin and cytokine signaling pathways. This disruption contributes to inflammation, bronchial epithelial dysfunction, and the proliferation of airway smooth muscle. B) miR-145-5p promotes the differentiation of Th2 cells and contributes to the manifestation of the Th2 phenotype. Variations in miR-145-5p levels, whether up-regulated or down-regulated, lead to alterations in RUNX3 expression in CD4⁺ T cells, which in turn affects cytokine levels. Inhibiting miR-145 may restore the Th1/Th2 balance that is often disrupted in asthma.

Fig. 5

Regulatory roles of miR-145-5p in pemetrexed-resistant in NSCLC. This figure has been redrawn from Ref. [99]. Prolonged treatment with chemotherapeutic agents such as pemetrexed can lead to the development of resistance in cancer cells. In this context, Sp1 is overexpressed, resulting in reduced sensitivity to pemetrexed, increased cell migration, and the upregulation of epithelial-mesenchymal transition (EMT)-related factors such as Snail and ZEB in A549 cells. Furthermore, the overexpression of BMI1 contributes to the upregulation of Sp1, which in turn suppresses the expression of miR-145-5p. This suppression promotes enhanced cell proliferation and elevates the levels of EMT-related transcription factors. However, these detrimental effects can be mitigated either by increasing the expression of miR-145-5p or by employing treatments that inhibit Sp1 activity.

Fig. 6

Impacts of miR-145-5p in regulating breast and prostate cancer. A) miR-145-5p targets SOX2 mRNA, resulting in degradation that inhibits BC cell proliferation. B) E-cadherin is the epithelial marker upregulated by miR-145-5p and reduced expression of the MMP-2 and MMP-9, which results in EMT induction and apoptosis in PC3 cells. In addition, miR-145-5p-activated caspase-9 that mediates apoptosis of the bone metastasis of PC3 cells. These figures have been redrawn from Refs. [137,144].