Cancer remains a significant global health issue due to its increasing cases and high mortality [1]. Despite progress in cancer research and improved detection and treatment methods, it continues to cause major societal and economic burdens [2]. Research is now focused on finding new biomarkers for early diagnosis and prognosis, as well as identifying potential therapeutic molecular targets. Non-coding RNAs (ncRNAs), including microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA), have emerged as significant epigenetic factors in cancer development and progression [3,4,5].

MicroRNAs are small non-coding RNA molecules, typically 19–25 nucleotides in length, that regulate gene expression post-transcriptionally. These molecules play critical roles in numerous biological processes, including cell growth, differentiation, apoptosis, and metabolism [6]. In the context of oncology, miRNAs have garnered significant attention for their intricate roles in tumorigenesis, acting either as oncogenes or tumor suppressors [7]. Dysregulation of miRNAs can impact a wide range of cellular pathways, leading to uncontrolled proliferation, evasion from apoptosis, angiogenesis, and metastasis. Additionally, due to their stability in bodily fluids, miRNAs hold promise as diagnostic and prognostic biomarkers, providing non-invasive tools to monitor disease progression and therapeutic response [8].

Long noncoding RNAs, which are over 200 nucleotides in length and do not encode proteins, are important in regulating transcription and other cellular processes [9, 10]. Circular RNAs, characterized by their unique circular structure and stability, play a role in gene regulation as miRNA sponges and are linked to cancer progression [11]. Their dysregulation can contribute to cancer by acting as oncogenes or tumor suppressors [12].

Among the myriad of miRNAs studied in oncology, miR-98 has risen to prominence owing to its intriguing roles in various human cancers. Initial studies reported differential expression of miR-98 in tumor tissues compared to adjacent normal tissues, hinting at its potential relevance in carcinogenesis. Research unveiled miR-98’s capacity to modulate multiple signaling pathways, influencing tumor growth, metastasis, and therapy resistance.

Several studies have indicated that miR-98 can act as both a tumor suppressor or an oncogene, depending on the cancer type and cellular context. Its multifaceted nature has led researchers to investigate its mechanistic roles and potential as a therapeutic target in greater depth [7].

This review aims to provide a comprehensive overview of the current knowledge surrounding miR-98 in the context of human cancer. We will explore the molecular and cellular mechanisms by which miR-98 contributes to cancer progression, its potential utility as a diagnostic and prognostic biomarker, and the emerging therapeutic strategies targeting this miRNA.

Basics of microRNA-98Biogenesis and molecular characteristics of miR-98

MiR-98 is an intronic miRNA found on chromosome X (Xp11.22) and one of the twelve members of the let-7 miRNA family [13]. MiR-98 is initially transcribed as primary miRNAs (pri-miRNAs) in the nucleus by RNA polymerase II. Primary miR-98 undergoes processing by the Drosha-DGCR8 complex, resulting in a precursor hairpin structure termed pre-miR-98 [14]. This precursor is then exported to the cytoplasm via Exportin-5, where it is further cleaved by the enzyme Dicer to generate the mature miR-98 molecule (Fig. 1) [15, 16].

Fig. 1

The process of miRNA biogenesis. Pre-miRNAs are created after RNAPII transcribes miRNA genes to pri-miRNAs, which are ultimately produced when Drosha cleaves pri-miRNAs. Pre-miRNAs are transferred to the nucleus and into the cytoplasm via Exportin5, where Dicer will turn them into mature miRNAs. The combination of mature miRNAs with AGO2 creates RISCs, which are essential for regulating gene expression

The length of mature miR-98-5p and miR-98-3p is 22 nucleotides [17, 18]. Its specific sequence and secondary structure contribute to its target recognition and binding properties. Notably, the “seed sequence” of miR-98, typically spanning nucleotides 2–8 from its 5’ end, plays a critical role in target mRNA recognition and binding [19].

Mature miRNAs miR-98-5p and miR-98-3p are produced from the opposite arms of the stem-loop of pre-miR-98 (Fig. 2A) [20]. The stability and functionality of these miRNAs vary in their biological characteristics. The “guide strand” miR-98-5p and the “passenger” strand miR-98-3p are produced by the miR-98 hairpin, as shown in Fig. 2B. Deep sequencing data indicates that miR-98-5p is more common than miR-98-3p [18, 21].

Fig. 2

(A) miR-98 family sequence structure. (B) It has two mature sequences, hsa-miR-98-5p (MIMAT0000096, miR-98-5p) and hsa-miR-98-3p (MIMAT0022842, miR-98-3p)

The biogenesis of miR-98 can be influenced by various cellular factors and conditions. For example, mutations or alterations in components of the Drosha or Dicer complexes can impact miR-98 maturation [22, 23]. Additionally, external factors like cellular stress or specific signaling pathways can modulate the expression and maturation of miR-98, highlighting the intricate regulatory network governing its biogenesis [24].

Physiological roles of miR-98 in cellular functions

Under normal physiological conditions, miR-98 often plays a role in regulating cellular growth. By targeting specific mRNAs involved in cell cycle progression, miR-98 can fine-tune the balance between proliferation and quiescence. MiR-98 has been implicated in cellular differentiation processes in various tissues [25]. For instance, in neuronal development, miR-98 may modulate the differentiation of neural progenitors into mature neurons by regulating key transcription factors or signaling molecules [26]. Additionally, the balance between cell survival and programmed cell death is crucial for tissue homeostasis. MiR-98 can influence this balance by targeting mRNAs associated with apoptosis, either promoting or inhibiting the process depending on the cellular context [27].

Furthermore, cells often encounter various forms of stress, such as oxidative stress, nutrient deprivation, or DNA damage. MiR-98 contributes to the cellular stress response by modulating the expression of stress-responsive genes, aiding in either cellular adaptation or the initiation of cell death pathways [28]. Emerging evidence suggests that miR-98, like other miRNAs, can be packaged into extracellular vesicles, facilitating intercellular communication. Through this mechanism, miR-98 may influence neighboring or distant cells, impacting tissue function and homeostasis [29].

Functional roles of miR-98 in cancer progression

MiR-98 plays a multifaceted role in cancer progression, exhibiting both oncogenic and tumor-suppressive properties, depending on the cancer context and microenvironment. Its dual role is exemplified by studies showing its contrasting functions in different cancer types (Fig. 3) (Table 1). For instance, while miR-98 suppresses tumor growth in lung cancer, it promotes breast cancer progression [30, 31].

Fig. 3

Comprehensive illustration of the interactions between miR-98 and its main target genes

Table 1 The potential targets of miR-98 and their functions in different cancers

MiR-98 has been identified as having a dual nature in tumorigenesis. Specifically, in certain cancer scenarios, it promotes tumorigenesis, as evidenced by researchers’ findings in gastric cancer, where overexpression of miR-98 led to increased cell growth and unfavorable patient outcomes [75]. This oncogenic potential might be driven by its ability to target and suppress tumor suppressor genes or pathways. Conversely, miR-98 has also been reported to function as a tumor suppressor, such as in hepatocellular carcinoma, where it inhibits oncogenic pathways or directly targets genes that drive tumorigenesis [69].

A variety of epigenetic elements are known to impact miR-98. Notably, current research is largely centered on how non-coding RNAs, such as lncRNA (long non-coding RNA) and circRNA (circular RNA), interact with miR-98 (Fig. 4).

Fig. 4

A detailed overview of LncRNAs’ interactions with miR-98 in human malignancies

MiR-98 has profound effects on cancer cell proliferation, apoptosis, and cell cycle regulation, according to research into its role in cellular mechanisms. It can modulate gene expression essential for cell growth, as exemplified by its ability to reduce cell proliferation in colorectal cancer cells, potentially via the IGF1R signaling pathway [98]. Apoptosis, a key mechanism in cancer control, is also influenced by miR-98. In glioma cells, miR-98 has been found to induce apoptosis by targeting the HMGA2 gene [99]. Moreover, its interaction with the cell cycle machinery can determine cell fate, with studies in cervical cancer revealing that its overexpression can induce G1 cell cycle arrest [91].

Furthermore, miR-98 plays a significant role in metastasis and angiogenesis, essential processes in cancer spread and growth. Through the regulation of EMT, miR-98 suppresses EMT and metastasis, as observed in bladder cancer, where it targets the IL-6/STAT3 signaling pathway [100]. Moreover, it can inhibit metastatic dissemination by regulating the degradation of the extracellular matrix, as evident in osteosarcoma, where miR-98 curbs metastasis by targeting MMP2 [101]. In pancreatic cancer, miR-98 has been shown to attenuate angiogenesis by directly targeting VEGFA, underscoring its role in vascular dynamics within tumors [102].

In conclusion, miR-98 emerges as a fundamental player in the complex landscape of cancer progression, dealing with tumorigenesis, cellular mechanisms, metastasis, and. Its role, whether tumor-promoting or tumor-suppressing, is highly dependent on the cancer type and microenvironment, emphasizing the necessity for context-specific therapeutic approaches targeting miR-98 in cancer treatment.

Patterns of miR-98 expression in different cancer typesBreast Cancer (BC)

BC is the most common cancer in women worldwide [103, 104]. At this point, targeted therapy, radiation therapy, chemotherapy, endocrine therapy, and surgical removal are the main methods of treatment [105]. Although the prognosis for breast tumors is improving, the condition is still the primary cause of mortality from cancer in women [103].

In breast cancer tissues and cell lines, miR-98 expression has been frequently reported to be downregulated. This reduced expression is often associated with more aggressive tumor subtypes and poorer patient prognoses. Notably, the level of miR-98 has been inversely correlated with metastatic potential in several breast cancer studies.

Researchers demonstrated the down-regulation of miR-98-5p in tumor tissues and MCF-7 breast cancer cells. Concurrently, they observed an up-regulation of Gab2, which countered by the transfection with miR-98-5p, led to significant inhibition of proliferation, migration, and invasion of MCF-7 cells [32]. Furthermore, other investigators elaborated on the oncogenic nature of Linc01287 that sponge miR-98-5p and the negative regulation of IGF1 by miR-98-5p, respectively. Overexpression of miR-98 or knockdown of Linc01287 resulted in an inhibitory effect on breast cancer cell progression, highlighting a potential therapeutic pathway in breast cancer treatment [33, 106].

The long noncoding RNA SNHG16 promoted breast cancer cell migration by acting as a competitive endogenous RNA (ceRNA) for E2F5 by binding with miR-98, while the miR-98-5p/IGF2 axis affected herceptin sensitivity in HER2 positive breast cancer. Specifically, upregulation of miR-98-5p led to decreased IGF2 expression, hence re-sensitizing herceptin-resistant cells [34, 35].

In a different perspective, experts revealed that submicron silica particles (SM-SiO2s) suppressed growth in various cancer cells, including breast cancer, by regulating the XLOC_001659/miR-98-5p/MAP3K2 pathway, suggesting a broader spectrum of miR-98-5p’s anti-cancer effects [66]. Additionally, it was found that miR-98 hindered proliferation, invasion, and migration while promoting apoptosis in breast cancer cells by targeting HMGA2, emphasizing the significance of miR-98 in controlling multiple facets of cancer progression [37].

Moreover, exploratory studies broadened the scope to lung cancer and the effects of newly synthesized heterosteroids on miRNA expressions in MCF-7 breast cancer cells respectively. It was found that aspirin treatment induced the expression of miR-98, depressing WNT1 in lung cancer cells [38]. It was noted that while tamoxifen up-regulated miR-98 expression, new heterosteroids significantly down-regulated it, suggesting a potential for reducing drug resistance [42].

Comprehensive analyses supported miR-98’s important role in regulating tumor growth, invasion, and angiogenesis by down-regulating ALK4 and MMP11, as well as its potential predictive value as a biomarker in breast cancer patients [39, 43]. A specific study explored the potential of miR-98 in predicting Sentinel Lymph Node Metastasis in ER+/HER2-breast cancer, developing a model that showed a significant association between miR-98 and SLNM, however, the direction of miR-98 regulation wasn’t detailed [106]. Additionally, it was demonstrated that dihydromyricetin could potentiate the efficacy of Herceptin in SKBR3 cells by up-regulating miR-98-5p, hence inhibiting IGF1R/HER2 dimer formation and consequently reversing Herceptin resistance [107].

MiR-98 was discovered to be differentially expressed in the HER2 + subtype across different breast cancer subtypes [108]. Employing algorithms, a regulatory interaction between miR-98 and the CD24 gene in breast cancer was identified, implying that miR-98 may play a functional role via CD24 targeting [40]. Deep sequencing also revealed a decrease in miR-98/Let-7 family miRNA expression in breast tumors compared to normal tissues, which aligns with the transition from noninvasive to invasive carcinomas [109].

The interaction between miR-98 and drug response was discovered, revealing that miR-98, along with other miRNAs, could affect docetaxel sensitivity [110]. Furthermore, estradiol (E2) induced the upregulation of miR-98 and other miRNAs in MCF-7 breast cancer cells, which resulted in a decrease in c-Myc and E2F2 protein levels, demonstrating miR-98’s role in the E2 response pathway in breast cancer scenarios [41]. The potential association of miR-98 with breast cancer was identified using network-based algorithms [111].

Downregulation of miR-98 in breast cancer biology has been linked to aggressive tumor subtypes and adverse patient outcomes. MiR-98 modulation could be beneficial in the treatment of breast cancer by influencing tumor growth, invasion, and drug responses. In addition to breast cancer, miR-98 could possibly be useful in the diagnosis, prognosis, and treatment of other cancers.

Lung cancer

Lung cancer is one of the most common cancers globally and contributes significantly to cancer-related death [112]. Based on their histological features, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) are the two main subtypes of lung carcinoma. The cause of about 85% of lung cancers is NSCLC [113]. Contrastingly, in certain subtypes of lung cancer, particularly non-small cell lung carcinoma (NSCLC), miR-98 has shown elevated expression. This upregulation has been linked to increased tumor growth and resistance to certain therapeutic agents, suggesting an oncogenic role in this context.

A specific study found that aspirin could improve lung cancer by targeting the miR-98/WNT1 axis. This targeted intervention reduced cell viability and formed malignant colonies. In lung cancer cells, aspirin activated miR-98, which decreased WNT1 expression. This discovery illuminates aspirin’s lung cancer treatment mechanism [38]. Similar studies have shown that miR-98 regulates several molecular interactions, including miR-98-5p/TGFBR1, ALG3, and PAK1. These regulatory interactions are crucial to lung cancer cell proliferation, migration, invasion, and apoptosis [45].

Several studies have found miR-98-related molecular networks, including the NEAT1/hsa-miR-98-5p/MAPK6 axis and the XLOC_001659/MAP3K2 pathway. The studies show that miR-98 affects lung cancer progression in a variety of cancer environments [44, 66]. Scientific studies on circular RNAs like circ_0048856 and circ_0006349, as well as interactions between integrin β3 (ITGB3) and miR-98, reveal challenging regulatory mechanisms. These interactions regulate lung cancer pathogenesis, including cisplatin resistance, malignancy, glycolysis, and in vivo tumor formation via targeting ITBG3 and MKP1 [47, 48, 54].

Researchers found a significant inverse relationship between lncRNA ANRIL and miR-98 in lung cancer cells, demonstrating that suppressing ANRIL increases miR-98 expression, preventing cisplatin resistance [114]. Another study found that lncRNA SNHG4 regulates miR-98-5p, affecting lung cancer cell proliferation, migration, and invasiveness [115].

Researchers also noted that miR-98 inhibits TWIST expression, which inhibits NSCLC cell migration and invasion, making it a potential tumor suppressor [46]. Jiang et al. and Ni et al. found that miR-98 modulates TGFBR1 and ITGB3 to inhibit cancer cell proliferation, migration, and invasion [48, 49]. Another study found that increasing miR-98 expression could hinder NSCLC progression by inhibiting the SALL4 protein [50].

Another example of complexity was uncovered in a study that identified a regulatory network involving miR-93, miR-98, and miR-197. These microRNAs impact the expression of the tumor suppressor gene FUS1, and an observed overexpression of miR-93 and miR-98 in small-cell lung cancer was documented [55]. Researchers found that curcumin suppressed lung cancer metastasis by increasing miR-98 expression, which downregulated LIN28A, MMP2, and MMP9 [55]. In another study, thiostrepton, an anti-cancer stem cell agent, increased tumor suppressor miR-98 levels to inhibit NSCLC cell growth and improve chemotherapy efficacy when combined with gemcitabine [52].

Researchers found that miR-98-3p was the least expressed dysregulated exosomal miRNA in lung adenocarcinoma (LUAD) patients. Although exosomal miR-7977 was the main focus as a novel biomarker for LUAD, LUAD patients had lower serum miR-98-3p than controls [116].

The researchers discovered that using a mimic to upregulate miR-98-5p reduced cell proliferation and increased apoptosis in NSCLC cells by targeting MAP4K3, indicating a potential pathway for suppressing NSCLC progression [5