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  • Review Article
  • OPEN ACCESS

Unraveling the Oncogenic Potential of microRNAs in Lung Cancer: A Narrative Review Article

  • Ali Moradi1,
  • Mohammad Bayat1,2,3,* ,
  • Parvin Pourmasoumi4 and
  • Sufan Chien2,3
 Author information 

Abstract

Lung cancer (LC) remains the leading cause of cancer-related deaths worldwide, characterized by high mortality rates and limited treatment options. MicroRNAs (miRNAs) are critical regulators of gene expression and play significant roles in the development of LC. This review aimed to provide a comprehensive analysis of oncogenic miRNAs involved in LC, focusing on their dysregulation, functional roles, and potential implications for diagnosis and therapy. In this review, we collected data from published literature, specifically selecting English articles closely related to the topic. We conducted a thorough review of studies published between 2013 and 2023, utilizing prominent academic databases such as PubMed, Scopus, and Google Scholar to gather relevant data. Our investigation highlights several oncogenic miRNAs that have been shown to play critical roles in lung cancer biology, including miR-9-5p, miR-21, and miR-31. These miRNAs are known to facilitate various key processes, such as tumor cell proliferation, enhanced migratory capabilities, and the development of resistance to chemotherapeutic agents. Additionally, miRNAs present significant diagnostic and therapeutic potential. In conclusion, the unique roles and regulatory networks of miRNAs in LC warrant extensive further research. Further research is essential to uncover the complex networks of miRNAs and to develop innovative miRNA-based therapies for lung cancer.

Keywords

Oncology, MicroRNA, miRNA, Oncogenic miRNA, Lung cancer, Cancer

Introduction

Lung cancer (LC) is a widespread and deadly disease, responsible for a significant number of cancer-related deaths worldwide. LC was first observed among miners in the nineteenth century, but it began reaching epidemic proportions in the early twentieth century. Over time, it has become one of the most common malignancies in men globally and a leading cause of cancer-related death.1 LC is a complex and heterogeneous disease characterized by the uncontrolled growth of abnormal lung tissue cells. It is primarily classified into two main types: non-small cell LC and small cell LC, each with distinct histological and molecular features.2–4 Several factors contribute to LC’s high mortality rate, including its high prevalence, late diagnosis, aggressiveness, limited treatment options, high recurrence and metastasis rates, drug resistance, and poor prognosis. It remains the most significant and lethal threat among all cancer types, with an estimated two million diagnoses and 1.8 million deaths annually. Lung neoplasms rank as the second most commonly diagnosed cancers in both men and women and are a leading cause of cancer-related death.5–7 Diagnosing LC involves a combination of clinical assessments, imaging techniques (such as chest X-rays and computed tomography), and histopathological examination of lung tissue samples obtained through biopsies or cytology. Recent advancements in liquid biopsies and molecular profiling techniques have revolutionized the field, enabling the detection of specific genetic alterations and the identification of targeted therapies.8–11 LC’s etiology is multifactorial, with genetic and environmental factors both playing direct roles in its development, resulting in a high degree of cellular and histological heterogeneity.12

The primary cause of LC, along with its geographical incidence and mortality patterns, is predominantly determined by tobacco smoking. Tobacco contains numerous carcinogens and toxic substances that can damage DNA in lung cells, which is a factor in the majority of cases. In recent years, public education and tobacco control policies have led to a decrease in LC incidence and mortality in the U.S. However, in many developing countries, LC rates are increasing due to the onset of the tobacco epidemic in these populations. Individual cigarette consumption remains the most prevalent risk factor for lung carcinoma.13 Other factors, including genetic susceptibility, occupational exposures, poor diet, air pollution, passive smoke inhalation, residential radon, infections, and genetic factors, may act independently or in concert with tobacco smoking in influencing the epidemiology of LC. Rapid economic development, urbanization, exposure to ambient particulate matter from industrial and vehicle exhausts, as well as occupational exposures to asbestos, polycyclic aromatic hydrocarbons, cooking fumes, radioactive products, and toxic metals, are strongly associated with the incidence of LC. Bacteria and viruses can also be important risk factors for LC. Despite these factors, tobacco smoking remains the major risk factor for LC.13–16 The interaction between genetic susceptibility and environmental factors can influence an individual’s risk of developing LC. It is important to note that some people without any known risk factors can still develop LC, highlighting the need for further knowledge, especially in areas such as early detection, metastasis, and recurrence of this disease. MicroRNAs (miRNAs) are small, non-coding RNA molecules that act as post-transcriptional regulators of gene expression. They bind to messenger RNA (mRNA) and can either inhibit translation or promote degradation. Dysregulation of miRNAs has been observed in various types of cancer, including LC. Recent studies have shown that miRNAs play a crucial role in regulating gene expression and are implicated in various aspects of cancer biology, including LC. Accumulating evidence suggests that certain miRNAs act as oncogenes, promoting tumor growth and metastasis.17–19 Specific miRNAs have been identified as responsible for the oncogenic transformation of LC cells, contributing to the development and progression of LC by targeting tumor suppressor genes or genes involved in cell cycle regulation, apoptosis, angiogenesis, and metastasis.20 For example, miR-21 is upregulated in LC and promotes cell proliferation, inhibits apoptosis, and enhances invasion and metastasis by targeting tumor suppressor genes such as PTEN, PDCD4, and RECK.21,22 Another important oncogenic miRNA in LC is miR-155, which is associated with a poor prognosis and increased tumor aggressiveness. miR-155 promotes LC cell growth, migration, and invasion by targeting multiple genes involved in cell cycle regulation, apoptosis, and epithelial-mesenchymal transition.23 This narrative review aimed to provide an overview of current knowledge regarding oncogenic miRNAs in human LC cells. It begins by highlighting the importance of understanding LC and its causes, followed by an explanation of miRNA biogenesis. For each miRNA, the review discusses its dysregulation in LC, its target genes, and the practical consequences of its aberrant expression. Specific examples of suppressive and oncogenic miRNAs extensively studied in LC are also discussed. This review aimed to contribute to the growing body of knowledge in the field of oncology and may pave the way for the development of new diagnostic tools and therapeutic strategies for this devastating disease.

Methodology

The data presented in this narrative review were obtained through a comprehensive search of the published literature. We focused on English-language articles closely related to the role of oncogenic miRNAs in LC. Relevant studies were identified through searches in PubMed, Scopus, and Google Scholar databases. The search strategy prioritized recent literature, with a primary focus on articles published from 2013 onward. Search terms included combinations of the following keywords: “Oncology”, “MicroRNA”, “Oncogenic miRNA”; “Lung Cancer”, and “Cancer”. Articles were selected based on their relevance to the review’s scope, with preference given to original research articles, reviews, and meta-analyses that provided detailed information on the mechanisms of action, clinical significance, or therapeutic potential of oncogenic miRNAs in LC. Articles were excluded if they were not in English, did not focus on LC, or primarily investigated non-oncogenic miRNAs.

miRNA biogenesis

Over the past two decades, the therapeutic potential of miRNAs has greatly expanded. miRNA biogenesis is a highly regulated and complex process involving multiple steps and factors (Fig. 1).

miRNA-Regulated Signaling Pathways in Lung Cancer: miRNAs can function as either tumor suppressors or tumor development (oncogenes).
Fig. 1  miRNA-Regulated Signaling Pathways in Lung Cancer: miRNAs can function as either tumor suppressors or tumor development (oncogenes).

Tumor-suppressive miRNAs inhibit oncogenic pathways, preventing cancer progression, while oncogenic miRNAs promote tumor growth by targeting tumor suppressor genes. miRNA, microRNA.

Any dysregulation in the miRNA biogenesis pathway can lead to changes in gene expression and the development of various diseases, including cancer. Understanding the mechanisms of miRNA biogenesis is crucial for developing new diagnostic and therapeutic strategies for miRNA-related diseases. miRNAs are small, non-coding regulatory RNA molecules that play a significant role in regulating gene expression by targeting specific mRNAs and binding to them, resulting in the silencing of the respective mRNA. The biogenesis of miRNAs involves several steps, including transcription, processing, and maturation. Due to their involvement in metastasis development, researchers have conducted extensive investigations into potential therapeutic applications.24,25 The canonical pathway of miRNA biogenesis begins with the transcription of miRNA genes by RNA polymerase II. These miRNA genes are typically located in intergenic regions or within introns of protein-coding genes. The primary transcript of miRNA, known as pri-miRNA, is a long, single-stranded RNA molecule that can consist of thousands of nucleotides. Pri-miRNAs feature a stem-loop structure recognized by the RNase III enzyme Drosha and its cofactor DGCR8 complex. This microprocessor complex cleaves the pri-miRNA at the base, generating a hairpin-shaped RNA molecule called pre-miRNA, typically 70–100 nucleotides long. The pre-miRNA is then exported from the nucleus to the cytoplasm by the exportin-5 protein. In the cytoplasm, further processing by the RNase III enzyme Dicer cleaves the loop of the hairpin pre-miRNAs, producing a double-stranded RNA molecule known as the miRNA duplex. One strand of the miRNA duplex, called the guide strand, is incorporated into the RNA-induced silencing complex. The RNA-induced silencing complex, comprising Argonaute proteins and associated factors, is responsible for target recognition and silencing. The guide strand of the miRNA duplex binds to the target mRNA through base pairing, leading to mRNA degradation or translational repression. The biogenesis of miRNAs is tightly regulated at multiple levels, including transcriptional, post-transcriptional, and epigenetic mechanisms. The expression of miRNA genes can be regulated by transcription factors, DNA methylation, and chromatin remodeling. Additionally, the processing and maturation of miRNAs can be influenced by RNA-binding proteins and other regulatory factors.26–31 Recent studies have revealed that miRNAs can be encapsulated and protected from degradation by exosomes. Exosomal miRNAs can be directly transferred to target cells, modulating various biological processes. Recent evidence indicates that exosomal miRNAs play a crucial role in modifying the microenvironment of LC, affecting drug resistance, angiogenesis, cancer progression, invasion, and metastasis.32 Moreover, miRNAs can target and inhibit many regulators in cells, including programmed cell death controllers like Bcl-2 and Mcl-1, TRAIL, Fas, p53, and the endoplasmic reticulum apoptotic pathways.33 Dysfunctions and alterations in miRNA biogenesis can disrupt the expression of oncogenic or tumor-suppressive target genes, significantly contributing to the establishment and progression of various human cancers. Numerous miRNAs have been identified as either downregulated or upregulated in human cancers, where they act as oncogenic or tumor-suppressive agents. Correlations between cancer detection, progression, staging, response to therapies, and miRNA expression have been found in human cancers, particularly in LC.25,34,35

Tumor suppressor miRNAs

In recent years, miRNAs have been associated with various biological processes, such as the development, invasion, and metastasis of many human cancers. miRNAs can act as either oncogenes or tumor suppressor genes, and DNA mutations or defects in cancer cells can lead to alterations in miRNA expression. Previous studies have highlighted the significant role of miRNAs in lung cancer epigenetics, angiogenesis, metastasis, apoptosis, as well as the inactivation of tumor suppressor genes and activation of oncogenes.36–42 Moreover, dysregulation of miRNAs is frequently observed in various types of cancer and often occurs through different mechanisms, including genetic alterations, epigenetic modifications, disruption of signaling pathways, and changes in miRNA biogenesis. Perturbations in key components of miRNA biogenesis, such as Drosha or Dicer, can contribute to miRNA dysregulation in cancer and affect the expression of target genes involved in cancer biology.43–45 Understanding the roles of miRNAs as oncogenes and tumor suppressors in cancer may potentially lead to the development of innovative strategies for diagnosis and treatment. Targeting dysregulated miRNAs could serve as a promising therapeutic approach for cancer treatment.46 Fundamentally, miRNAs play essential roles in cancer development and progression. Tumor suppressor miRNAs act as negative regulators of oncogenic pathways, while oncogenic miRNAs promote tumor growth and metastasis.47 Previous research has revealed a strong correlation between miRNA expression and intracellular levels of reactive oxygen species (ROS) in many cancers. miRNAs can modulate the generation of ROS, and, conversely, ROS can regulate the expression of miRNAs. ROS can promote tumor progression, metastasis, and resistance to chemotherapy. When ROS levels exceed a certain threshold, they can increase genomic instability and lead to cell death.48 Numerous studies have provided substantial data suggesting that tumor suppressor miRNAs can inhibit the expression of oncogenes and other genes involved in promoting cell proliferation, invasion, migration, angiogenesis, epithelial-to-mesenchymal transition, and metastasis. These miRNAs are often downregulated or dysregulated in cancer cells, resulting in the upregulation of their target genes and the promotion of oncogenic processes. Additionally, tumor suppressor miRNAs are involved in the regulation of immune checkpoints, contributing to tumor cells escaping immune surveillance and creating a microenvironment conducive to their growth and progression.39,49–52 Epigenetic changes, such as DNA methylation and chromatin structure alterations, play a significant role in silencing various genes, including tumor suppressor genes. These alterations can lead to reduced miRNA expression in LC.53 Over the past two decades, numerous studies have identified a variety of miRNAs involved in LC. In this context, we will highlight some of the most extensively studied and important examples of tumor-suppressive miRNAs in LC in Table 1.54–62

Table 1

Examples of tumor-suppressive miRNAs in LC

miRNANatural role
Let-7Able to inhibit the expression of oncogenes that involved in cell proliferation and invasion in human LC cells54
miR-34it’s one of the a tumor suppressor miRNAs that act via targeting the several cell cycle proteins55
miR-126Has powerful ability to inhibit the LC cells proliferation56,57
miR-128It can regulate the angiogenesis and lymph-angiogenesis via targeting VEGF-C58
miR-181Suggesting miRNA-181 may be have as a tumor suppressor by inhibition relates to higher Bcl-2 levels59
miR-195Its expression enhances in the tumor tissues in patients with LC and has a tumor-suppressive functions60
miR-200Identified as a potent suppressors for lung adenocarcinoma metastasis61
miR-451Ectopic expression significantly suppressed the proliferation and formation of LC cells62

Bcl-2, B-cell lymphoma 2; LC, lung cancer; miRNA, microRNA; VEGF-C, vascular endothelial growth factor C.

Moreover, several studies have shown that numerous miRNAs act as tumor-suppressive miRNAs, especially in LC. Recent reviews have noted that miR-1, miR-7, miR-23b, miR-98, miR-142, miR-144, miR-145, miR-149, miR-150, miR-125a,63 and miR-513-3p, miR-382, miR-19a-3p, miR-99b-5p, miR-590-5p, miR-106-5p, miR-186 belong to the category of tumor-suppressive miRNAs.46 Additionally, other studies have suggested that certain miRNAs, including miR-15a, miR-16, miR-26, miR-29, miR-134, miR-138, miR-218, miR-203, miR-320, miR-449a,43 as well as miR-30e, miR-30a-5p, miR-133b, miR-145-3p/5p, miR-146a, miR-148a, miR-206, miR-373, miR-379, miR-488, miR-512, miR-520f, miR-590, and miR-944, are also recognized as tumor-suppressive miRNAs.64

Tumor oncogenic miRNAs

Recent research has indicated that oncogenic miRNAs constitute a novel class of molecular drivers that play essential roles in the development and progression of human cancers. These oncogenic miRNAs specifically influence LC. In LC, certain miRNAs exhibit oncogenic properties, promoting tumor cell growth and metastasis. Oncogenic miRNAs may be either upregulated or downregulated in LC cells compared to normal lung cells. They target multiple genes involved in various cellular processes, including cell proliferation, apoptosis, invasion, and angiogenesis. Examples of oncogenic miRNAs in LC are provided in Table 2.65–84

Table 2

Examples of oncogenic miRNAs in LC

miRNANatural role
miR-9-5pPromotes lung adenocarcinoma cell proliferation, migration and invasion65
miR-10bOverexpression promotes LC cell proliferation and invasion66
miR-17-92 clusterOverexpression of the miR-17-92 cluster with occasional gene amplification plays a role in the LCs67
miR-21one of the most famous oncogenic miRNAs, and it is over-expressed in a number of malignancies68
miR-31Increased expression of miR-31 reduced the BAP1, leading to cell proliferation and suppressed apoptosis69
miR-93Promotes cancer progression by targeting PTEN70
miR-103a-3pPromotes the progression of LC via Akt signaling71
miR-127Drove a pronounced shift from the epithelial to the mesenchymal phenotype in cancer cells72
miR-135bHigh expression of miR-135b enhanced cancer cell invasive and promoted metastasis73
miR-155It promotes tumor growth and metastasis by targeting multiple genes of cell proliferation, invasion74
miR-183-5pInvolved in the progression of a wide variety of human cancers75
miR-197-3pExpression was upregulated in serum exosomes of LC patients and lung tissues76
miR-208amiR-208a exerts oncogenic functions in the carcinogenesis and progression of NSCLC77
miR-210Its overexpression could promote LC progression78
miR-221miRNA-221 plays an important role in occurrence and development of tumor79
miR-224miR-224 expression promoted LC cell migration and invasion80
miR-324-5p/3pSignificantly promoted cell proliferation and invasion in LC cells81
miR-328-5pInfluences cell growth and migration to promote LC progression by targeting LOXL482
miR-484Promotes non-small-cell LC progression through inhibiting Apaf-183
miR-494-3pmiR-494-3p overexpression is correlated with the development, improvement and prognosis of tumors84

Akt, protein kinase B; BAP1, BRCA1 associated protein-1; LC, lung cancer; LOXL4, lysyl oxidase-like 4; miRNA, microRNA; NSCLC, non-small cell lung cancer; PTEN, phosphatase and tensin homolog.

Dysregulation in the expression of these miRNAs, observed in various LC subtypes, can contribute to tumor initiation, metastasis, progression, disrupt diagnosis, and increase drug resistance. Understanding the intricate regulatory networks involving miRNAs and their target genes is essential for unraveling the complex mechanisms underlying LC progression.85–88 Furthermore, oncogenic miRNAs have proven valuable as diagnostic and prognostic biomarkers in LC. Their dysregulated expression in tissue samples, blood, and other body fluids makes them promising candidates for early detection and monitoring cancer progression. The association between specific oncogenic miRNAs and clinical outcomes suggests their potential as prognostic indicators, aiding in treatment stratification and personalized therapy.89,90 Additionally, understanding the role of oncogenic miRNAs in LC can provide insights into the molecular mechanisms underlying the disease and potentially lead to the development of targeted therapies. The therapeutic use of oncogenic miRNAs in LC is also noteworthy. Targeting these miRNAs has shown promising results in preclinical models. By silencing or inhibiting oncogenic miRNAs, it is feasible to restore the expression of tumor-suppressive miRNAs or sensitize cancer cells to chemotherapy, ultimately improving treatment outcomes.91–93 As miRNAs play a significant role in the development and progression of LC, dysregulation of specific miRNAs contributes to oncogenic processes, and targeting these miRNAs holds therapeutic potential. Additionally, miRNAs can serve as diagnostic and prognostic markers in LC. Further research is needed to fully understand the complex regulatory networks involving miRNAs in LC and to develop effective miRNA-based therapies. This review aimed to contribute to the growing body of knowledge in the field of oncology and potentially pave the way for the development of novel diagnostic tools and therapeutic strategies for this devastating disease. Numerous studies have revealed that aberrant miRNA expression plays a crucial role in the LC process. Here, we will highlight some of the most extensively studied and essential oncogenic miRNAs strongly associated with LC:

Oncogenic miRNAs in LC

miR-9-5p

One of the oncogenic miRNAs in LC is miR-9-5p, which mediates the development of certain cancers by regulating various mRNAs. A study by Zhu et al.65 focused on miR-9-5p and its role in lung adenocarcinoma, showing a significant increase in miR-9-5p levels in lung carcinoma. Generally, miR-9-5p acts as an oncogene in LC, promoting cell proliferation and migration. Preclinical studies have shown that targeting miR-9-5p can inhibit proliferation in lung cancer cell lines.65

miR-10b

Liu et al.66 examined the oncogenic miRNA miR-10b and revealed its upregulation following binding to its promoter, which in turn led to a reduction in the levels of HOXD10 and E-cadherin. miR-10b acts as a tumor invasion factor in LC cells, enhancing carcinoma progression by targeting the klotho protein, a receptor for Fibroblast Growth Factor-23, which is also a prominent therapeutic target. miR-10b promotes metastasis in LC through the regulation of epithelial-to-mesenchymal transition. Research has demonstrated that inhibiting miR-10b can reduce metastasis in lung adenocarcinoma models.66

miR-17-92 cluster

Several recent studies have highlighted the miR-17-92 gene cluster, a well-conserved cluster containing six members: miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, and miR-92a. This cluster, the first discovered oncogenic miRNA cluster, plays a critical role in LC cell biogenesis. Overexpression of this cluster, often due to gene amplification, promotes cell growth and survival in LC cells. Preclinical models have highlighted that silencing members of this cluster leads to reduced tumor growth and enhanced apoptosis in lung cancer.67,94–96

miR-21

Yang et al.68 reported that miR-21 is overexpressed in various human malignancies, including LC. Upregulation of miR-21 in LC correlates with cancer extent in the body and lymph node metastasis. Additionally, the status of serum miR-21 expression appears to be an independent prognostic factor for LC. Inhibitors targeting miR-21 have demonstrated the ability to enhance chemosensitivity in LC models. Recent studies indicate that downregulating miR-21 can lead to increased apoptosis and improved responses to chemotherapeutic agents.68

miR-31

Continuing to elucidate the role of oncogenic miRNAs in LC, miR-31, as reported by Yu et al.,69 is another essential oncogenic miRNA often overexpressed in human LC. It regulates cell invasion and metastasis by targeting specific tumor suppressor genes or activating signaling pathways in cells. Research has shown that inhibiting miR-31 can reduce cell migration and invasion in vitro and in vivo, suggesting that targeting miR-31 may hinder metastasis and improve overall survival in LC patients.69

miR-93

Numerous studies have identified miR-93 as an oncogenic miRNA in various types of human cancers, including LC. Dysregulation of miR-93 biogenesis is associated with tumor progression and metastasis. The downregulation of various tumor suppressor genes mediated by miR-93 is responsible for these effects. Moreover, miR-93 targets PTEN to promote cancer progression, and its overexpression has been observed in LC tissue cells and plasma of patients, suggesting its potential as an important biomarker for early-stage LC. Preclinical studies demonstrated that blocking miR-93 decreases LC cell viability and increases apoptosis, indicating that targeting miR-93 could enhance treatment efficacy and mitigate chemotherapy resistance.70,97–99

miR-103a-3p

In a study by Li et al.,71 the oncogenic miRNA miR-103a-3p was found to promote LC progression via the Akt signaling pathway by targeting PTEN. The role of the miR-103a-3p/PTEN/Akt signaling cascade suggests that miR-103a-3p is a novel therapeutic target for LC treatment. In preclinical experiments, the inhibition of miR-103a-3p sensitized LC cells to standard chemotherapy, suggesting that therapeutic strategies targeting this miRNA could improve treatment outcomes.71

miR-125b

The study by Li et al.100 highlighted miR-125b, the human homologue of lin-4, which has been reported to play a role in tumor progression. miR-125b acts as a regulator of apoptosis and proliferation in tumor cells. In LC, serum miR-125b levels significantly increase and strongly correlate with LC stages and patient survival. Reintroduction or mimicking of miR-125b has been shown to enhance sensitivity to gefitinib in LC cells, indicating its potential as a therapeutic target to overcome resistance.100

miR-127

Elevated levels of miR-127 have been associated with the induction of epithelial-to-mesenchymal transition in cancer, rendering cells resistant to epidermal growth factor receptor inhibitors and enhancing their tumor multiplication potential. Restoring miR-127 expression has been linked to reduced tumor growth in preclinical models, highlighting its potential in therapeutic applications.72

miR-135b

Dysregulation of miR-135b plays a critical role in tumor progression. miR-135b is essential for osteogenic cell development and is linked to the progression of various cancer types, including LC. miR-135b is regulated by DNA demethylation and specific nuclear factor signaling. Abnormal expression of miR-135b in cancer may result from inflammation and epigenetic modifications. Inhibiting miR-135b has demonstrated antitumor effects by reducing cell proliferation and invasion, making it a promising candidate for therapeutic targeting.73

miR-155

miR-155 enhances the development of LC by downregulating SOCS1, SOCS6, and PTEN. Some studies have suggested an inverse correlation between miR-155 expression levels and recovery, as well as disease-free survival in LC patients. Furthermore, miR-155 promotes tumor growth and metastasis by targeting genes involved in cell proliferation, invasion, and immune regulation. Trials are exploring the use of anti-miR-155 therapies in combination with immune checkpoint inhibitors, aiming to enhance the anti-tumor immune response in LC patients.74

miR-183-5p

miR-183-5p, when overexpressed, is strongly implicated in the progression of various human cancers, including ovarian, breast, and cervical cancers. It also exhibits strong potential as a convenient diagnostic and therapeutic target in cancer treatments. Research indicates that inhibiting miR-183-5p can suppress tumor growth and enhance chemosensitivity, highlighting its potential as a therapeutic target.75

miR-197-3p

miR-197-3p is predominantly upregulated in serum exosomes and cancer tissues of LC patients. These exosomes transport miR-197-3p from LC cells to vein endothelial cells, leading to their proliferation, angiogenesis, and migration. Additionally, miR-197-3p promotes lung tumor growth and angiogenesis. Studies show that targeting miR-197-3p can decrease LC cell growth and increase efficacy against chemotherapy, indicating its role as a viable therapeutic target.76

miR-208a

Another oncogenic miRNA is miR-208a, which plays an essential role in the carcinogenesis and progression of LC. It achieves these effects by directly targeting SRCIN1 and regulating the ERK pathway. Therefore, miR-208a may offer a promising potential target for treating LC patients. Evidence suggests that inhibiting miR-208a could disrupt pathways critical for tumor growth, presenting it as a potential therapeutic target.77

miR-210

An essential oncomir in LC is miR-210, which is significantly increased in LC cells. Its overexpression has been shown to elevate LC progression, and it is hypothesized that miR-210 contributes to LC progression by targeting LOXL4. Targeting miR-210 has shown promise in reducing tumor growth under hypoxia, suggesting it may be beneficial in treating hypoxic tumors in LC patients.78

miR-221

miR-221 has been found to promote LC growth and invasion by repressing the expression of TIMP2 (Tissue inhibitor of metalloproteinase 2). Some researchers have suggested that inhibiting miR-221 could be a valuable target for LC treatment.79,101–103 Recent transcriptome sequencing analysis has revealed that several miRNAs, such as miR-224, miR-324-5p, and miR-328-5p, play significant roles in promoting the progression, proliferation, survival, invasion, and migration of LC cells, severely implicating the pathogenesis of LC. The potential of anti-miR-221 therapies is being investigated to enhance responses to conventional treatments, particularly in LC.80–82

miR-484

Another miRNA associated with oncogenic miRNA signatures in LC is miR-484. Li et al.83 have shown that miR-484 participates in the regulation of cancer cell proliferation. Additionally, some studies have suggested that miR-484 plays a vital role in the development of tumor growth. Preclinical research is exploring the role of miR-484 modulation in LC, aiming to understand its impact on treatment outcomes and tumor aggressiveness.83

miR-494-3p

Recent research has also highlighted miR-494-3p, which can activate the PI3K/AKT pathway by targeting PTEN. Overexpression of miR-494-3p has been extensively observed in various human tumors, including LC, and is closely related to tumor development, progression, and prognosis. Targeting miR-494-3p has been shown to enhance the sensitivity of LC cells to treatment, indicating its potential application in improving therapeutic outcomes.84

Therefore, it is imperative to explore and understand the relevance of miRNAs, especially oncogenic miRNAs and tumor-suppressive miRNAs, in LC. Understanding the molecular mechanisms of these miRNAs in the LC metastasis process and their roles in treatment strategies is of paramount importance. Future research is needed to unravel the complex regulatory networks of other oncogenic miRNAs and tumor-suppressive miRNAs and their targets, which may open up new avenues for cancer diagnosis and treatment.

Author’s opinion: As research continues to shed light on the specific roles of oncogenic miRNAs, it becomes increasingly clear that these molecules could serve as critical biomarkers and therapeutic targets in the fight against LC. Developing miRNA-based therapeutics, such as miRNA mimics or inhibitors, could offer a novel approach to combating LC by restoring normal gene expression pathways disrupted during tumorigenesis. This approach could not only enhance therapeutic efficacy but also reduce resistance often encountered with conventional chemotherapies, thereby improving patient outcomes. Overall, the exploration of miRNAs in LC not only deepens our understanding of the disease’s molecular underpinnings but also opens new avenues for innovative therapies and more effective clinical strategies. Moreover, the identification of specific miRNA profiles associated with different lung cancer subtypes could lead to more personalized treatment strategies.

Future prospects

Therapeutic targeting of oncogenic miRNA

Future research could focus on developing innovative therapeutic strategies that specifically target oncogenic miRNAs implicated in lung cancer. This could involve designing novel inhibitors or anti-microRNA molecules that selectively block the function of these miRNAs, thereby inhibiting cancer progression and improving patient outcomes. Key Area: Develop innovative therapeutic strategies that specifically target oncogenic miRNAs in LC. Current Gaps: Lack of highly specific and deliverable anti-miRNA therapies; limited understanding of off-target effects.

Biomarker discovery and personalized medicine

Exploring the role of miRNAs as potential biomarkers for lung cancer could provide valuable insights into disease prognosis, treatment response, and patient stratification. By identifying specific microRNA signatures associated with different lung cancer subtypes, researchers may be able to tailor treatment plans to individual patients, ultimately leading to more personalized and effective therapeutic approaches. Key Area: Explore miRNAs as biomarkers for LC prognosis, treatment response, and patient stratification. Current Gaps: Lack of validated miRNA signatures with strong predictive power; challenges in standardizing miRNA detection methods.

Non-invasive detection and monitoring

Advancements in technology and methodology could pave the way for the development of non-invasive methods for detecting and monitoring microRNA expression levels in lung cancer patients. Liquid biopsies, such as circulating miRNA in blood samples, could offer a less invasive and more accessible approach to monitoring disease progression, assessing treatment response, and predicting patient outcomes. Key Area: Develop non-invasive methods for detecting and monitoring miRNA expression in LC patients. Current Gaps: Low concentration of circulating miRNAs; challenges in isolating and quantifying miRNAs from liquid biopsies; limited understanding of miRNA stability in circulation.

Exploration of novel miRNA regulators and signaling pathways

Continued research into novel miRNA regulators and signaling pathways involved in lung cancer could unveil new targets for therapeutic intervention. By investigating the intricate network of interactions between miRNAs and their target genes, researchers may identify key players driving oncogenic processes in lung cancer, ultimately leading to the development of more targeted and effective treatment strategies. Key Area: Uncover novel miRNA regulators and signaling pathways involved in LC. Current Gaps: Incomplete understanding of miRNA-mRNA interactions; limited knowledge of the upstream regulators of miRNA expression.

Integration of bioinformatics and systems biology approaches

The integration of bioinformatics and systems biology approaches could enhance our understanding of the complex role of miRNAs in lung cancer pathogenesis. By utilizing computational tools and high-throughput sequencing technologies, researchers can unravel the intricate regulatory networks controlled by miRNAs, leading to the identification of novel therapeutic targets and biomarkers for lung cancer. Key Area: Enhance our understanding of the complex role of miRNAs in LC pathogenesis through computational analysis. Current Gaps: Complexity of miRNA regulatory networks; difficulty in integrating large-scale omics datasets; lack of user-friendly tools for miRNA data analysis.

Controversies and gaps

There is a significant gap between the promising results observed in preclinical studies and the outcomes in clinical trials. Many miRNA-based therapies demonstrate efficacy in vitro or in animal models, but translating these findings to human patients has proven difficult. This raises questions about the reliability of preclinical models and the biological complexity of human tumors. miRNAs can regulate multiple target genes, leading to potential off-target effects that could result in unintended consequences. This raises concerns about the safety profile of miRNA therapies. The controversy lies in how to effectively predict and manage these off-target effects while ensuring therapeutic efficacy. Although the roles of specific miRNAs in LC are being studied, comprehensive understanding of their functional networks and interactions within the tumor microenvironment is still limited. More research is needed to clarify how miRNAs influence tumor behavior and response to therapies. Identifying reliable biomarkers for predicting patient response to miRNA-based therapies remains a significant gap. The mechanisms through which LC cells may develop resistance to miRNA-based therapies are not well understood. LC is a highly heterogeneous disease, and the variability in patient responses to miRNA therapies is not fully characterized.

Conclusions

In conclusion, miRNAs are pivotal in LC development and progression. Dysregulated miRNAs drive oncogenic processes, offering therapeutic potential. miRNAs also serve as diagnostic and prognostic markers in LC. The limited sample sizes and variability in study designs can hinder the generalizability of findings, highlighting the need for large-scale clinical trials to confirm the relevance of specific miRNAs as potential oncogenic drivers in LC. More research is required to understand the complex miRNA regulatory networks and to develop effective miRNA-based therapies. This review augments our knowledge of oncology and could catalyze novel diagnostic and treatment strategies for LC. Several critical oncogenic miRNAs in LC, such as miR-9-5p, miR-10b, miR-17-92, miR-21, miR-31, miR-93, miR-103a-3p, and miR-125b, impact diverse LC aspects. Understanding their roles and mechanisms is vital for LC diagnosis and treatment. Exploring intricate miRNA networks and their targets is imperative for potential advancements in cancer care.

Declarations

Acknowledgement

None.

Funding

The authors confirm that they did not receive any financial support for this review article.

Conflict of interest

Dr. Mohammad Bayat is a Senior Scientist, and Dr. Sufan Chien is the CEO of Noveratech LLC, based in Louisville, CA, USA. The authors declare that there is no other conflict of interest associated with this work.

Authors’ contributions

Study concept and design (AM, MB), acquisition of data (AM, MB, PP, SC), analysis and interpretation of data (AM, MB, PP, SC), drafting of the manuscript (AM, MB), critical revision of the manuscript for important intellectual content (AM, MB), administrative, technical, or material support (AM), and study supervision (MB). All authors have made a significant contribution to this study and have approved the final manuscript.

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Moradi A, Bayat M, Pourmasoumi P, Chien S. Unraveling the Oncogenic Potential of microRNAs in Lung Cancer: A Narrative Review Article. Cancer Screen Prev. Published online: Mar 19, 2025. doi: 10.14218/CSP.2025.00001.
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January 4, 2025 February 26, 2025 March 5, 2025 March 19, 2025
DOI http://dx.doi.org/10.14218/CSP.2025.00001
  • Cancer Screening and Prevention
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Unraveling the Oncogenic Potential of microRNAs in Lung Cancer: A Narrative Review Article

Ali Moradi, Mohammad Bayat, Parvin Pourmasoumi, Sufan Chien
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