The role of MAPK pathway in gastric cancer: unveiling molecular crosstalk and therapeutic prospects

Abstract

Gastric cancer remains a significant health burden globally, especially prevalent in Asian and European regions. Despite a notable decline in incidence in the United States and Western Europe over recent decades, the disease’s persistence underscores the urgency for advanced research in its pathogenesis and treatment strategies. Central to this pursuit is the exploration of the mitogen-activated protein kinase (MAPK) pathway, a pivotal cellular mechanism implicated in the complex processes of gastric cancer development, including cellular proliferation, invasion, migration, and metastasis. The MAPK or extracellular signal-regulated kinase pathway serves as a crucial conduit for transmitting extracellular signals to elicit intracellular responses, with its signaling cascades subject to alterations due to genetic and epigenetic variations across various diseases, prominently cancer. This review delves into the intricate role of the MAPK signaling pathway in the pathogenesis of gastric cancer, drawing upon the most recent and critical studies that shed light on MAPK pathway alterations as a gateway to the disease. It highlights the pathway’s involvement in Helicobacter pylori-mediated gastric carcinogenesis and the tumorigenic processes induced by the Epstein-Barr virus, showcasing the substantial influence of miRNAs and lncRNAs in modulating gastric cancer’s biological properties through their interaction with the MAPK pathway. Furthermore, the review extends into the therapeutic arena, discussing the promising impacts of herbal medicines, MAPK pathway inhibitors, and immunosuppressants on mitigating gastric cancer’s progression. Through an exhaustive examination of the MAPK pathway’s multifaceted role in gastric cancer, from molecular crosstalks to therapeutic prospects, this review aspires to contribute to the ongoing efforts in understanding and combating this global health challenge, paving the way for novel therapeutic interventions and improved patient outcomes.

Background

Gastric cancer stands as the fifth most prevalent malignancy worldwide and ranks as the third leading cause of oncology-related mortality [1], characterized by a median survival duration of less than 12 months in patients with advanced stages of the disease [2]. The occurrence of gastric cancer exhibits notable disparities across genders and geographical regions, with the incidence rate in males being roughly double that of females [3]. Significantly, approximately half of the newly diagnosed cases of gastric cancer emerge from developing nations. Infection with Helicobacter pylori (HP) and Epstein-Barr virus (EBV) are critical pathogenic factors in the development of gastric cancer. The diagnostic approaches for HP infection encompass both invasive and non-invasive techniques. Invasive methods include histology, the rapid urease test, and bacterial culture, while non-invasive options consist of serological assays and the urea breath test, among others [4] (Table 1). Historically, EBV detection was predominantly carried out using in situ hybridization (ISH) techniques; however, due to their high cost and complex procedural requirements, these methods are not widely employed in routine clinical practice [5–7].Currently, the diagnosis of EBV infection relies primarily on serological and molecular biological tests. However, serological markers such as IgM are not detectable in the early stages of infection, and polymerase chain reaction (PCR) can be influenced by antiviral treatments, limiting its diagnostic accuracy [8]. Recent studies suggest that circulating cell-free EBV DNA demonstrates superior sensitivity and specificity for the diagnosis of EBV-associated gastric cancer (EBVaGC), though the sample sizes in these studies remain limited [9]. These diagnostic methods each have distinct sensitivities, specificities, and limitations, as outlined in Table 1.

Table 1.

A summary of diagnostic methods for HP- and EBV-associated gastric cancer

Diagnostic test	Applicable pathogens	Sensitivity	Specificity	Limitations	Materials Reference
Urea breath test	HP	> 95%	> 95%	Specific conditions (cool temperature, microaerophilic conditions), high cost of commercial kits, lack of expertise, and restrictions by national authorities to acquire the substrate	[10, 11]
Stool antigen test	HP	96%	97%	Differences in antigens used in different geographic regions may cause heterogeneity of results	[12, 13]
Serological tests	HP	85%	> 80%	Cannot distinguish between current and past infections	[14, 15]
Rapid urease test	HP	80–90%	93–100%	Positive results should be confirmed by a second test	[16, 17]
Culture	HP	70–90%	100%	Specific transport conditions, laboratory skills, and equipment	[4, 18]
Histopathology	HP	> 95%	99%	Higher costs, very operator-dependent	[18, 19]
PCR	HP	96%	98%	High cost and skill requirement, false-positive results due to detection of DNA fragments of dead bacteria	[20, 21]
ISH	EBV	> 95%	100%	High cost and complex procedures	[5–7]
PCR	EBV	62.87%	100.00%	It is susceptible to antiviral drugs	[8]
Viral capsid antigen IgM	EBV	21.56%	100.00%	It has not been produced or is insufficiently produced in the early stage of the disease	[8]
Circulating cell-free EBV DNA	EBV	71.4%	97.1%	Limited clinical sample size	[9]

In a comparative study of the 5-year survival rates for stomach cancer across various countries, Matsuda and Saika [22] observed that survival rates in Japan surpass those observed in other regions, suggesting differences in medical practices, early detection strategies, and therapeutic approaches. Recent trends indicate a decline in the incidence of gastric cancer [23], potentially linked to decreased smoking rates and advancements in early diagnosis through endoscopic techniques, facilitating the prompt identification and excision of cancerous lesions. Predominant risk factors include genetic predisposition, dietary habits, and exposure to exogenous infectious agents [24, 25], with the HP and, to a lesser extent, the EBV significantly contributing to the risk profile for gastric cancer [26]. Several studies have evaluated the distribution of various risk factors in the Chinese population [27–29]. Cumulative evidence was graded according to the Venice criteria, with the attributable risk percentage (ARP) used to assess the epidemiological impact of these factors [27]. Among the identified risk factors, the edible hot food is found to contribute the most significant proportion to the overall risk [27], while Epstein-Barr virus (EBV) accounts for the smallest proportion [29] (Table 2). However, these statistical findings are derived from two different analytical methods, and further research is necessary to conduct a more comprehensive and in-depth investigation into these data.

Table 2.

The percentage of risk factors associated with gastric cancer

Participants who developed gastric cancer	Statistical methods	Percentage (%)	Materials Reference
HP-infection	ARP	38.27	[27]
EBV-infection	Percentage method	3.4	[29]
High salt diet	ARP	43.53	[27]
Pickled food	ARP	54.75
Fast eating	ARP	45.36
Irregular meals	ARP	41.52
Edible hot food	ARP	57.81
Smoked and frying	ARP	49.75
Spicy diet	ARP	42.20
Smoking	ARP	21.88
Genetic predispositions	ARP	46.52

Recent advances have significantly deepened our understanding of gastric carcinogenesis, improving patient survival rates through novel therapies, with pathological analyses revealing numerous mutations in gastric cancer tissues that disrupt critical signaling pathways [30], particularly the mitogen-activated protein kinase (MAPK) pathway, pivotal to tumor initiation and progression. The present review focuses on the roles of MAPK in the gastric cancer, unraveling molecular crosstalks, and shed light into possible novel targets and strategies for clinical treatment.

The regulation of MAPK signaling pathway

MAPKs play pivotal roles in cellular responses to a variety of external stimuli, including growth factors, inflammatory agents, cytokines, and environmental shifts, in addition to mediating intercellular interactions [31]. The MAPK signaling cascade represents one of the most anciently evolved signaling pathways, characterized by a series of phosphorylation events leading to specific cellular responses upon activation. This cascade typically initiates with the activation of MAPK kinase kinase (MAPKKK), notably the Raf isoforms, which subsequently phosphorylates and activates MAPK kinase (MAPKK), culminating in the activation of MAPK [32, 33]. The MAPK pathway, ubiquitous across eukaryotic life forms, orchestrates a broad spectrum of cellular functions, including gene expression regulation, mitosis, cell metabolism, proliferation, apoptosis, and other pivotal cellular activities [34].

Extensive research has demonstrated that the MAPK signaling pathway critically governs the proliferation, migration, and invasion capabilities of gastric cancer cells. Mutations within this pathway have been linked to abnormal activities in various forms of gastric cancer [35–37]. Notably, mutations in key kinases within the RAS/RAF/MAPK signaling cascade, such as Rat sarcoma (RAS) and Rapidly Accelerated Fibrosarcoma (RAF) kinases, are frequently observed in gastrointestinal tumors and gastric polyps [38–40]. MicroRNAs (miRNAs) serve as modulators of RAS signaling, often showing amplification during gastric cancer progression [41, 42]. Furthermore, both miRNAs and long non-coding RNAs (lncRNAs) target components of the MAPK pathway, playing instrumental roles in the advancement of stomach cancer [43]. The intricate regulatory mechanisms employed by miRNAs and lncRNAs significantly contribute to the proliferation, invasion, and metastasis of gastric cancer [44], positioning these molecules as potential genetic biomarkers for cancer diagnostics, prognosis, and therapeutic targeting [45, 46].

As illustrated in Fig. 1, providing a comprehensive overview of the intricate molecular interplay underpinning gastric cancer pathogenesis and progression. The MAPK pathway, a complex network of signaling cascades, is intricately activated by a variety of stimuli such as G protein-coupled receptors, an array of growth factors, diverse environmental triggers, and a spectrum of inflammatory cytokines. These elements converge to initiate the MAPK pathway, setting in motion a series of biochemical events critical for cellular function. This detailed illustration outlines the four central signaling pathways within the MAPK framework: ERK5, ERK, JNK, and p38/MAPK. The ERK5 pathway, also known as Mitogen-Activated Protein Kinase 7, alongside ERK (Extracellular Signal-Regulated Kinase), JNK (Stress-Activated Protein Kinase), and p38/MAPK (p38 Kinase), forms the backbone of this signaling network. These pathways are interconnected through a variety of molecular intermediaries, including β-arrestin, which acts as a β-suppressor protein, MKP (Mitogen-Activated Protein Kinase Phosphatase), and MKK3/6 (Mitogen-Activated Protein Kinase Kinase 3/6). Furthermore, the roles of RAS, a small G protein pivotal in cell signaling, RAF (Rapidly Accelerated Fibrosarcoma), a kinase implicated in cancer progression, and MEK (Mitogen-Activated Protein Kinase/ERK Kinase), serve as critical junctions in the transduction of signals that regulate cellular responses to external and internal cues.

Fig. 1.

Activation and signaling pathways of the MAPK Cascade: an overview of stimuli, cascades, and downstream targets: this detailed illustration outlines the four central signaling pathways within the MAPK framework: ERK5, ERK, JNK, and p38/MAPK. The ERK5 pathway (Mitogen-Activated Protein Kinase 7), alongside ERK (Extracellular Signal-Regulated Kinase), JNK (Stress-Activated Protein Kinase), and p38/MAPK (p38 Kinase), constitutes the core of this signaling network. These pathways are interconnected through a variety of molecular intermediaries, such as β-arrestin (β-suppressor protein), MKP (Mitogen-Activated Protein Kinase Phosphatase), and MKK3/6 (Mitogen-Activated Protein Kinase Kinase 3/6). Additionally, RAS (a pivotal small G protein in cell signaling), RAF (Rapidly Accelerated Fibrosarcoma, a kinase associated with cancer progression), and MEK (Mitogen-Activated Protein Kinase/ERK Kinase), serve as critical junctions in the transduction of signals that regulate cellular responses to external and internal cues

MAPK signaling pathway in Helicobacter pylori–induced gastric cancer

Gastric cancer is a complex, multifactorial disease with over fifty identified risk factors. Inflammation, atrophy of the gastric mucosa, and intestinal metaplasia resulting from HP infection have been closely linked to a heightened risk of developing gastric cancer [47, 48]. On December 21, 2021, the U.S. Department of Health and Human Services officially recognized chronic HP infection as a human carcinogen in the 15th edition of the Carcinogens Report. H. pylori, a gram-negative, rod-shaped, aerobic, spiral bacterium, exhibits high prevalence rates among immigrants from countries with widespread infection [49]. The global prevalence of HP during 2015–2022 was 43.9% in adults and was 35.1% in children and adolescents [50]. Despite the significant benefits of anti-HP treatment, population-based screening and eradication strategies are not currently incorporated into China’s national cancer prevention plans. Additionally, the rise in antimicrobial resistance has led to a decrease in treatment efficacy, necessitating revised guidelines that emphasize antibiotic stewardship [51, 52].

The pathogenesis of gastric cancer involves intricate interactions among HP-specific virulence factors, host genetics, and environmental influences [53]. HP’s ability to persistently colonize the stomach’s acidic environment, due to its enzymatic and virulence factors, alters gastric acid secretion—an effect that promotes carcinogenesis. During the initial infection phase, HP secretes urease, enabling colonization by neutralizing stomach acidity. This bacterium also triggers the phosphorylation of cytotoxin-associated gene A (CagA), activating gastric epithelial cells to express the cytosolic receptor Rev-Erbα, thereby initiating the ERK signaling pathway [54, 55]. This activation leads to NF-κB binding to the Rev-erbα promoter, enhancing bacterial colonization [56, 57]. Moreover, ammonia and carbonic acid produced by urease activity alter the microenvironment's pH, affecting bacterial viability, HP utilizes its flagellum to penetrate the mucus layer and colonize the gastric mucosal surface, where it is protected from acidity and contributes to biofilm formation [58]. The bacterial flagellum, along with other virulence factors like vacuolating cytotoxin A and CagA, elicits humoral responses post-infection [59].

Persistent inflammation caused by HP triggers Correa’s cascade (Fig. 2), leading from chronic inflammation to gastric atrophy, chemosis, and eventually to precursor lesions and tumors [60]. The internalization of the CagA protein by gastric epithelial cells sets off a chronic inflammatory response, underpinning the bacteria’s carcinogenic potential. A suite of adhesins facilitates H. pylori’s adherence to the host cell surface, enabling the formation of a Type IV secretion system (T4SS). Through this system, CagA is translocated into the host cell cytoplasm, where it engages in critical interactions with SHP2 phosphatase or the junction protein Grb2. These interactions are instrumental in activating signal transduction pathways that lead to the upregulation of interleukin-8 (IL-8) and the activation of activator protein-1 (AP-1) via the Ras/Raf/extracellular signal-regulated kinase (ERK) cascade. Once activated, ERK undergoes nuclear translocation, where it phosphorylates and activates the transcription factor ELK1. The activation of ELK1, in concert with serum response factor (SRF), binds to the serum response element (SRE) on DNA, thereby driving the expression of the proto-oncogenes c-Fos and c-Jun, which are crucial for cell cycle progression and proliferation.

Fig. 2.

Oncogenic Role of H. pylori in Gastric Cancer Pathogenesis: The internalization of the CagA protein by gastric epithelial cells triggers chronic inflammation, amplifying its carcinogenic effects. Various adhesins enable H. pylori to attach to host cells, establishing a Type IV secretion system (T4SS) that translocates CagA into the host cytoplasm. Inside the cell, CagA interacts with SHP2 phosphatase or Grb2, activating pathways that increase interleukin-8 (IL-8) and stimulate AP-1 via the Ras/Raf/ERK cascade(including NK-κB and MAPK pathways). Once activated, ERK translocates to the nucleus to phosphorylate ELK1, which, in conjunction with serum response factor (SRF), binds to the serum response element (SRE) on DNA, thereby enhancing the expression of proto-oncogenes c-Fos and c-Jun, which are essential for cell cycle progression and proliferation. In a parallel signaling cascade, cortactin phosphorylation activates focal adhesion kinase (FAK), leading to further phosphorylation events. Additionally, PAR1b inhibits guanine nucleotide exchange factor-H1 (GEF-H1) specificity for RhoA, thereby activating the c-Jun N-terminal kinase (JNK) pathway. This cascade enhances cell proliferation, cytoskeletal reorganization, and inflammation, all contributing to tumorigenesis

In a parallel pathway, the phosphorylation of cortactin, a key cortical actin-binding protein, triggers the activation of focal adhesion kinase (FAK), leading to further phosphorylation events. Moreover, the phosphorylation induced by PAR1b, also known as a microtubule affinity-regulated kinase, plays a significant role in modulating cellular dynamics. It achieves this by inhibiting the specificity of guanine nucleotide exchange factor-H1 (GEF-H1) for RhoA, thereby stimulating the c-Jun N-terminal kinase (JNK) pathway. This activation results in enhanced cell proliferation, cytoskeletal reorganization, and a robust inflammatory response, all of which contribute to the advancement of tumorigenesis.

Recent studies suggest that Host-HP interactions are predominantly mediated by virulence factors that trigger MAPK signaling of host cells, regulating the proliferation of gastric epithelial cells, evading immune surveillance, and generating a chronic inflammatory state [61].As mentioned earlier, tyr-phosphorylated-CagA lures SHP2,resulting in modifications of intracellular signaling that enhance the proliferation rate of gastric epithelial cells through a sustained activation of the Ras/ERK MAPK pathway [62]. Furthermore, CagA can interact with an adaptor protein like GRB2, thus allowing recruitment of the RAS GTPase exchange factor to the plasma membrane, thereby promoting cellular proliferation and scattering [63]. The increase in the mutation rate driven by hyperproliferation, coupled with chronic inflammation, is intrinsically linked to gastric cancer development. Again, CagA induces AP-1 activation via the Ras/Raf/ERK pathway. Concurrently, phosphorylated ERK activates NF-κB and MAPK, which translocates from the cytosol to the nucleus, further activating IL-8 gene expression(Fig. 2), thereby promoting the development of gastric cancer [64].HP infection enhances some substances promotes the progression of gastric cancer by upregulating MAPK pathway expression, and suppresses HP infection could reverse mucosal atrophy and prevent lesions in intestinal metaplasia and dysplasia by suppressing MAPK pathway. For example, HP infection enhances heparanase leading to cell proliferation via MAPK signalling in human gastric cancer cells [65], and berberine inhibits gastric cancer cells proliferation and IL-8 expression in vitro and in vivo, associated with the inactivation of the MAPK signaling pathway [66].In summary, HP infection influences deeply not only the proliferative status of the gastric epithelia but also induces chronic inflammation through the MAPK pathway, setting the stage for gastric carcinogenesis.

MAPK signaling pathway in EBV–induced gastric cancer

The Cancer Genome Atlas (TCGA) project has delineated a molecular taxonomy for gastric cancer (GC), categorizing it into four distinct subtypes: EBV-positive tumors, microsatellite instability-high (MSI-H) tumors [67], genomically stable tumors, and tumors exhibiting chromosomal instability. Epstein-Barr virus (EBV), a ubiquitous human herpesvirus harboring double-stranded DNA, is implicated in multiple malignancies, including approximately 8% to 10% of gastric cancers [68]. Remarkably, over 95% of the global adult population harbors EBV asymptomatically [68].The TCGA classification underscores an emerging significance of EBV-positive and MSI-H subtypes in GC, particularly in relation to programmed death ligand-1 (PD-L1) expression [69, 70], which is often correlated with poor prognosis and reduced overall survival among patients in East Asia, despite some reports of favorable outcomes [71].

EBV’s encoded proteins are intricately linked to the MAPK signaling pathway within the cell cycle. The virus encodes three latent membrane proteins: LMP1, LMP2A, and LMP2B. LMP1, recognized for its oncogenic transformation capabilities, has been evidenced to immortalize human primary B lymphocytes into lymphoblastoid cell lines (LCL), likely via ERK and p38 activation in the MAPK pathway which inhibits dual-specificity phosphatases 6 (DUSP6) and 8 (DUSP8), thereby facilitating LCL proliferation [72, 73]. The detailed exposition of how EBV orchestrates tumorigenesis via the MAPK signaling pathway, leveraging its oncogenic potential to manipulate host cellular mechanisms in Fig. 3. The activation of LMP1cascade results in the downregulation of dual-specificity phosphatases, DUSP6 and DUSP8, which are critical regulators of MAPK signaling and serve to attenuate the pathway under normal physiological conditions. Concurrently, LMP1 promotes the expression of SP1, a transcription factor that plays a key role in the transcriptional regulation of various genes involved in cell growth and differentiation. Furthermore, LMP1 exerts an inhibitory effect on EphA4, a member of the Eph family of receptor tyrosine kinases, thereby contributing to the suppression of cellular proliferation and fostering a conducive environment for viral-induced oncogenesis. Simultaneously, LMP1 has been implicated in inducing gastric epithelial-to-mesenchymal transition (EMT) through ERK/MAPK pathway and recruiting fibroblasts in vitro, leading to increased epithelial cell invasiveness and a myofibroblast-like phenotype transformation [74, 75].In addition to manipulating the MAPK signaling pathway, EBV exploits other molecular mechanisms to promote its oncogenic agenda. The virus enhances the expression of BGLF2 and BZLF1, proteins involved in EBV lytic cycle activation, through the JNK pathway. This leads to the activation of AP-1, a transcription factor that further facilitates viral activation and replication, thereby amplifying EBV's oncogenic effects.

Fig. 3.

EBV-Driven Oncogenesis: Manipulating MAPK Signaling and Apoptotic Pathways: EBV promotes tumorigenesis through the MAPK signaling pathway, manipulating host cellular mechanisms. The latent membrane protein 1 (LMP1), a crucial EBV oncoprotein, activates MAPK components—ERK, JNK, and p38—downregulating dual-specificity phosphatases DUSP6 and DUSP8 that normally inhibit this signaling. Simultaneously, LMP1 enhances SP1 expression, regulating genes linked to cell growth and differentiation, and inhibits EphA4, suppressing cellular proliferation and creating a favorable environment for viral oncogenesis. Additionally, EBV increases BGLF2 and BZLF1 expression via the JNK pathway, activating AP-1 to promote viral replication and bolster its oncogenic effects. EBV transforms B cells and induces apoptosis via the JNK/p38 pathway. By regulating CD70 and CD47 expression, EBV activates signaling cascades that cause the activation of the endoplasmic reticulum (ER) stress response, ultimately leading to apoptosis

With regard to LMP2A and LMP2B, although LMP2A's involvement in the MAPK signaling pathway is established, by activating EBV-positive phosphorylation of ERK in gastric cancer cell lines, inhibits aryl hydrocarbon receptor expression [76], the precise mechanisms and molecular interactions remain elusive, and reports regarding the relationship between LMP2B and MAPK are notably absent. Therefore, further studies are imperative to elucidate the relationship between LMP2A, LMP2B and MAPK signaling.

EBV's ability to transform B cells and induce apoptotic pathways is also mediated through the JNK/P38 pathway (Fig. 3). By modulating the expression of CD70 and CD47 on B cells, EBV triggers signaling cascades that lead to the activation of the endoplasmic reticulum (ER) stress response, culminating in apoptosis. In EBV-transformed B cells, heightened CD70 expression induces ER stress, activating JNK and p38 MAPK pathways and inducing ER stress-related genes [77]. Similarly, CD47 ligation on EBV-transformed B cells indirectly triggers ROS generation, leading to cell cycle arrest and subsequent activation of the p38 MAPK/JNK pathway via ER stress [78, 79]. This strategy not only aids in EBV’s evasion of host immune surveillance but also contributes to the pathogenesis of EBV-associated malignancies, including gastric cancer.

The link between EBV infection and GC was first described in 1990 by Burke et al. [80]. The molecular profile of EBVaGC is that of EBV driving DNA hypermethylation, frequent phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations, and the overexpression of Janus kinase 2, PD-L1and PD-L2 [81].Recently, TCGA network identified EBVaGC as a distinct subgroup, the activation of immune signaling pathways represents another key characteristic [82]. Across the gastric tumor samples from TCGA cohort, the expression of ERK/MAPK gene sets was found to be high in the EBV subtypes of gastric tumors [83]. Meanwhile, several studies have indicated that miR-BART11-3p promotes cell proliferation, migration, and invasion by modulating DUSP6-MAPK axis in EBVaGC [84].But the relationship among EBV pathogenesis, MAPK signaling pathway, and gastric cancer remain scarcely documented in existing research, further exploration is needed.

MicroRNAs and the MAPK pathway in gastric cancer: mechanisms and therapeutic perspectives

MicroRNAs (miRNAs) are pivotal non-coding RNA molecules that play critical roles in cellular processes such as proliferation, differentiation, and apoptosis, and are deeply involved in the pathogenesis of various tumors, including gastric cancer. These highly conserved RNA molecules regulate gene expression predominantly by binding to the non-coding regions of target genes in signaling pathways, either inhibiting their translation or modulating the expression of target genes. The human miRNA-generating complex comprises Dicer and phospho-TRBP isoforms, with TRBP phosphorylation being mediated through the MAPK pathway [85]. This linkage underscores the association between miRNA dysregulation and the aberrant activation of the ERK/MAPK cascade in tumorigenesis.

In gastric cancer, mutations in upstream membrane receptors and signal transducers, such as EGFR and RAS proteins within the MAPK signaling pathway, may drive overactive MAPK signaling, leading to sustained signal transduction. Activating mutations in RAS are a hallmark of many human cancers, with miRNAs acting as crucial negative regulators. The let-7 miRNA family, which targets human RAS genes, all contain let-7 complementary sites, providing early functional evidence of the molecular connection between miRNA deregulation and oncogenic pathways [86, 87]. Subsequent research has identified several miRNAs that regulate RAS genes, influencing cell proliferation, migration, and cytoskeletal dynamics. Specifically, miR-214 targets the proto-oncogene N-ras [88], miRNA-96 downregulates KRAS reducing cancer cell invasiveness [89], and miRNA-128 modulates gastric carcinogenesis through MAPK signaling activation [90].

Contrary to miRNAs’ role as negative regulators, miR-21, a downstream miRNA effector, functions as an antagonist in the MAPK pathway by targeting multiple negative regulators of the Ras/MEK/ERK pathway, acting to block tumor suppressor genes [91]. Moreover, miR-181c targets KRAS, playing a pivotal role in gastric carcinogenesis through oncogenic RAS activation [92]. A comprehensive survey of miRNA signatures in a wide array of tumors highlighted a complex interplay between miRNAs and the MAPK signaling pathway, suggesting their key role in gastric carcinogenesis.

MiRNAs also participate in the p38 pathway-mediated signaling, adopting various roles in cancer and inflammation development. The upregulation of miR-17-92 emerges as an independent prognostic marker in gastrointestinal cancer [93], while miR-141 and miR-338 have been shown to inhibit the p38 signaling pathway and regulate key phosphorylation events [94, 95], respectively, thereby impacting gastric cancer growth and metastasis. Additionally, miR-1298-5p targets MAP2K6, influencing the MAP2K6/p38 MAPK axis to regulate autophagy and tumor growth, positioning miR-1298-5p as a potential specific regulator of the p38 pathway [96]. However, given the varied results from different tumor models, further comprehensive studies are necessary to elucidate the precise role of miRNAs in the p38 signaling pathway.

In drug-resistant gastric cancer, RAS-gene mutations typically diminish the effectiveness of targeted therapies and contribute to treatment resistance. Studies have linked miR-939 expression with increased chemoresistance and tumor recurrence in gastric cancer by modulating the SLC34A2/Raf/MEK/ERK pathway, enhancing chemosensitivity to 5-fluorouracil [96]. MiR-122 has been shown to regulate the RAS/RAF/ERK signaling pathway by targeting IGF-1R, thereby influencing resistance to sorafenib in tumor cells [97]. These findings highlight the impact of miRNA alterations on the efficacy of targeted treatments, potentially reshaping therapeutic strategies for gastric cancer (Table 3, Fig. 4).

Table 3.

A comprehensive list of miRNAs that regulate the MAPK pathway

Signalling Pathways	Micro-RNA	Target	Role in gastric cancer	Materials Reference
MAPK	miR-26a-5p	KPNA2	Weifuchun suppresses the malignancy of gastric cancer cells by targeting KPNA2 through miR-26a-5p-mediated destabilization and the deactivation of the MAPK signaling pathway	Stomach cancer cells [98]
ERK/mapk	miR-BART11-3p	DUSP6	Epstein-Barr virus-encoded miR-BART11-3p modulates the DUSP6-MAPK axis to promote gastric cancer cell proliferation and metastasis	Stomach cancer cells [84]
RaS/mapk	MiR-1278	CALD1	MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway	Stomach cancer cells [99]
Raf/MEK/erk	microRNA-939	SLC34A2	Decreased MIR-939 expression levels were associated with drug-resistant tumour recurrence in gastric cancer patients, and elevated levels were associated with inhibition of 5-fluorouracil sensitivity in gastric cancer	Stomach cancer [100] patients
MAPK/fak	microRNA-19a/miR-96	KIF26A	MiR-19a/miR-96-mediated KIF26A can inhibit gastric cancer migration and invasion by regulating focal adhesion pathways and inhibiting EMT	Stomach cancer [101] patients
RaS/mapk	microRNA-181a-5p	RASSF6	Reduced expression levels of miR-181a-5p were associated with gastric cancer cell proliferation, cell cycle transition and gastric cancer progression	Stomach cancer [102] patients
ERK/mapk	microRNA-622/miR-197	LAMC2/CD82	Dysregulation of miRNA-622/197 is associated with gastric cancer cell invasion and gastric cancer progression	Stomach cancer [103] Patients stomach cancer cells
ERK/mapk	microRNA-302b	CDK2	The elevated level of microRNA-302b expression was associated with lymph node metastasis, metastatic distance and TNM stage of gastric cancer	Stomach cancer Patients [104] Stomach cancer cells
MEK/ERK/mapk	microRNA-199a/b-3p	PAK4	Reduced levels of microRNA -199a/b-3p expression were associated with gastric cancer cell proliferation and gastric cancer progression	Stomach cancer cells [105]
MEK/ERK/ p38 MAPK	microRNA-141	MACC1	Reduced microRNA-141 expression levels are associated with cellular staging, lymph node metastasis, and gastric cancer progression	Stomach cancer cells [104]

Fig. 4.

Expression Analysis of Identified Risk Factors in Gastric Cancer Using TCGA and GTEx Databases, with Correlation Validation of Genes and miRNAs. Use the TCGA Expression Database and the TCGA combined with the GTEX database to perform expression analysis on identified risk factors (genes, miRNAs, etc.) and validate the correlation and correlation coefficients of certain genes and miRNAs in gastric cancer

LncRNAsin gastric cancer: MAPK pathway and therapeutic targets

Long non-coding RNAs (lncRNAs) are increasingly recognized as vital regulators in various biological processes, including cellular proliferation, migration, apoptosis, metastasis, epithelial-mesenchymal transition (EMT), and drug resistance in gastric cancer [102, 106, 107]. These molecules, longer than 200 nucleotides, exert their influence through transcriptional and post-transcriptional modifications, impacting gene expression. The MAPK pathway, a critical signaling cascade in gastric cancer, is one such process modulated by lncRNAs, highlighting their importance in cancer biology [108, 109].

Among the newly identified plasma lncRNA biomarkers for gastric cancer are BANCR, TINCR, CCAT2, AOC4P, and LINC00857, each playing a unique role in the disease's pathogenesis. BANCR is noted for its upregulation in gastric cancer cells, where its suppression leads to inhibited MEK, ERK, and JNK signaling activities [110, 111]. This results in a marked reduction in cancer cell proliferation and migration by dampening the activation of p38MAPK and JNK and modulating the MAPK cascade response. Moreover, BANCR has been implicated in inducing EMT through a MEK/ERK-dependent pathway and enhancing cisplatin resistance in gastric cancer cells via the ERK1/2 pathway [112]. These findings suggest that targeting BANCR could offer a novel therapeutic approach for gastric cancer. TINCR, by interacting with BRAF, enhances kinase activity and consequent MAPK pathway activation [113]. CCAT1, whose expression is elevated across various tumors, plays a role in promoting cancer cell proliferation and metastasis, potentially through the regulation of the MAPK pathway [114, 115]. The silencing of CCAT1 not only inhibits proliferation and induces cell cycle arrest but also decreases the phosphorylation levels of key components in the MAPK pathway [116, 117], such as MAPK, ERK, and MEK. lncRNA AOC4P, found to be overexpressed in gastric cancer tissues compared to adjacent non-cancerous tissues, when inhibited, reduces gastric cancer cell proliferation, migration, and invasion, and potentially promotes apoptosis by lowering the expression levels of ERK1, JNK, and p38 proteins. Similarly, LINC02253, by increasing the stability of KRT18 mRNA, influences gastric cancer cell growth, migration, and invasion through the activation of the MAPK/ERK signaling pathway [118, 119].

These novel lncRNAs linked to gastric cancer pathogenesis offer promising new avenues for research, targeting mechanisms of disease occurrence, development, and prognosis. However, the roles of TINCR and the poorly studied CCAT1 and CCAT2 in gastric cancer remain to be fully elucidated. Thus, extensive fundamental research is required to unravel the complex functions and mechanisms of lncRNAs in gastric cancer, presenting an exciting frontier for therapeutic innovation and understanding cancer biology (Table 4).

Table 4.

A comprehensive list of LncRNAs regulating the MAPK pathway

Signaling Pathway	IncRNA	Role in gastric cancer	Materials	Reference
MAPK / ERK	LINC02253	LINC02253-mediated mRNA methylation is associated with the growth and metastasis of gastric cancer	Stomach Cancer Patients Stomach cancer cells	[120]
MAPK/erk /jnk/p38	lncRNA BANCR	The expression level of BANCR was associated with the proliferation, migration, EMT and drug resistance of gastric cancer cells	Stomach Cancer Patients Stomach cancer cells Animal models	[110]
MAPK / ERK /jnk/p38	LINC00858	The high expression of LINC00858 is related to the proliferation, migration, tumour growth rate and spread of gastric cancer cells	Stomach Cancer Patients Stomach cancer cells	[121]
MAPK/ERK	lncRNA BCAR4	The high expression of LncRNA BCAR4 is related to the proliferation and apoptosis of gastric cancer cells	Stomach Cancer Patients Stomach cancer cells	[122]
MAPK/ERK	LINC00152	High expression of LINC00152 was associated with gastric cancer cell proliferation, apoptosis, cycle, migration and invasion	Stomach cancer cells	[123]
MAPK / ERK /jnk/p38	lncRNA AOC4P	High expression of lncRNA AOC4P was associated with gastric cancer cell proliferation, apoptosis, migration, apoptosis and invasion	Stomach Cancer Patients Stomach cancer cells	[124]
MAPK/ERK	lncRNA-PICART1	Low expression of lncRNA-PICART1 is associated with proliferation, apoptosis and tumor formation in gastric cancer cells	Stomach cancer cells	[125]
MAPK/JNK	lncRNA SNHG6	High expression of lncRNA SNHG6 was associated with proliferation, cellular senescence and tumor growth of gastric cancer cells	Stomach Cancer Patients Stomach cancer cells	[126]
MAPK/jnk/erk	lncRNA CASC2	Low expression of lncRNA CASC2 was associated with cell proliferation and tumor growth in gastric cancer cells	Stomach Cancer Patients Stomach cancer cells	[127]
MAPK	IncRNA KCNKI5-ASI	Low expression of IncRNA KCNKI5-ASI was associated with proliferation, apoptosis of gastric cancer cells	Stomach Cancer Patients Stomach cancer cells	[128]
MAPK/ERK	IncRNA Neat1_2	High expression of IncRNA Neat1_2 is associated with apoptosis and tumor growth in gastric cancer cells	Stomach cancer cells	[129]
MAPK	lncRNA MAP3K1-2	High expression of lncRNA MAP3K1-2 was associated with proliferation, invasion and prognosis of gastric cancer cells	Stomach Cancer Patients Stomach cancer cells	[130]
MAPK	LINC 00483	High expression of LINC 00483 was associated with proliferation, invasion, and metastasis of gastric cancer cells	Stomach cancer cells	[131]
MAPK/ERK	IncRNA DUSP5P1	IncRNA DUSP5P1 expression is associated with gastric cancer cell proliferation, cell cycle, apoptosis, tumor growth and metastasis	Stomach Cancer Patients Stomach cancer cells Animal models	[132]

Herbal medicine and MAPK in gastric cancer: molecular and therapeutic insights

In gastric cancer, herbal medicines have emerged as promising agents that can inhibit cell proliferation and induce apoptosis through the modulation of key signaling pathways. A series of experimental studies have demonstrated the potential of various herbal compounds to interfere with critical molecular pathways involved in gastric cancer progression.

For instance, Berberine hydrochloride has been shown to significantly reduce the viability of gastric cancer cells, such as MGC 803, in a dose- and time-dependent manner. Further investigations revealed that berberine inhibits the phosphorylation of p38 MAPK, ERK1/2, and JNK, even at low concentrations, with the downregulation of these signaling molecules playing a key role in its anticancer effects [66, 133]. Another study highlighted that berberine also suppresses the growth of human gastric cancer BGC823 cells both in vitro and in vivo by inducing autophagy inhibition via the MAPK/mTOR/p70S6K and Akt pathways [134].

Additionally, the Chinese dragon’s blood ethyl acetate extract (CDBEE) has been reported to activate the MAPK signaling pathway, contributing to the inhibition of proliferation and metastatic potential of gastric cancer cells, including MGC-803 and HGC-27. This pathway activation induces both apoptosis and autophagic cell death in these cells [135].Among traditional Chinese herbal compounds, danshenone stands out. Specifically, Danshenone IIA promotes the phosphorylation of p-p38 and p-JNK while reducing the expression of p-ERK. This compound may induce cell cycle arrest in gastric cancer cells by upregulating p-p38, p-JNK, p53, and p21, and downregulating CDC2 and cyclin B1 [136, 137]. Moreover, Cudraxanthone L, isolated from Cudrania tricuspidata, regulates the MAPK signaling pathway to inhibit the invasion, migration, and colony formation of gastric cancer MGC803 cells. It also blocks the S phase of the cell cycle and induces apoptosis in these cells [138].

The therapeutic potential of classical Chinese medicine has also been explored in the context of precancerous lesions, where its constituents act on multiple cellular targets [139]. For example, the administration of Xianglian Wan (XLP) has been shown to regulate the expression of p38 MAPK in gastric cancer mouse models [140]. In a similar vein, Hulupolide-I induces GADD45α expression in a p53-independent manner and activates the JNK/p38 MAPK signaling pathway, which forms a positive feedback loop that mutually regulates both pathways [141]. Additionally, Elian granules and compounds derived from Dendrobium ferruginous have demonstrated efficacy in animal models by targeting the JNK and p38 pathways. A curcumin derivative (L6H4) has been reported to inhibit the proliferation and invasion of gastric cancer BGC-823 cells [142], white atractylodes extract has also shown promise in modulating caspase activity and regulating the MAPK pathway, effectively inhibiting the migration of gastric cancer AGS cells [143]. Furthermore, bioactive ingredients such as baicalin and toosendanin modulate the MAPK pathway and exhibit notable anticancer effects [144], the compound lobetyol, isolated from Lobelia chinensis, induces apoptosis and cell cycle arrest in gastric cancer MKN45 cells in a time- and dose-dependent manner, with the MAPK signaling pathway mediating these effects [145]. These findings collectively suggest that MAPK signaling plays a crucial role in the anticancer mechanisms of these herbal compounds, highlighting their potential for inhibiting tumor growth and metastasis [146, 147].

In recent years, compound synthetic Chinese medicine formulas have gained attention for their synergistic effects. One example is CCMH, a formula composed of alfonbufagin (11.14%), cinobufotalin (18.67%), cinobufophalin (7.33%), cinobufagin (16.67%), resibufogenin (16.74%), hingin (8.45%), vicine (12.03%), and telocinobufagin (8.97%). This formula has demonstrated the ability to inhibit gastric cancer cell proliferation, induce cell cycle arrest, promote apoptosis, and cause MMP breakdown by regulating key proteins in the PI3K/Akt and MAPK signaling pathways [148].

The interplay of Chinese herbal medicines in regulating key signaling pathways such as MAPK in gastric cancer underscores the potential of these compounds in oncology. Despite promising outcomes, the precise molecular mechanisms through which these herbal constituents exert their oncogenic and therapeutic effects remain to be fully elucidated. Therefore, further clinical trials and animal studies are essential to validate the effectiveness of Chinese herbal medicine in cancer treatment, offering a less toxic and cost-effective alternative with minimal side effects. This underscores the importance of continued research to explore the therapeutic prospects of Chinese medicine in cancer, particularly in understanding the active ingredients and their mechanisms of action (Table 5).

Table 5.

Herbal medicines targeting MAPK pathway in gastric cancer

Herbal medicine/compound	Target pathway/protein	Mechanism of action	Effect on gastric cancer	References
Berberine Hydrochloride	p38 MAPK, ERK1/2, JNK	Inhibitsphosphorylation of p38 MAPK, ERK1/2, and JNK	Reduces viability of MGC 803 cells in a dose- and time-dependent manner; induces apoptosis	[66, 133]
CDBEE (Chinese Dragon's Blood Ethyl Acetate Extract)	MAPK signaling (p38 MAPK, JNK)	Induces apoptosis and autophagic cell death by activating MAPK pathway	Inhibits proliferation and metastasis in MGC-803 and HGC-27 cells	[135]
Danshenone IIA	p38 MAPK, JNK, ERK	Upregulates p-p38 and p-JNK, downregulates p-ERK; induces cell cycle arrest	Promotes cell cycle arrest in gastric cancer cells	[136, 137]
Cudraxanthone L	p38 MAPK	Regulates MAPK pathway, inhibits cell migration and colony formation	Inhibits invasion, migration, and colony formation; induces apoptosis	[138]
Xianglian Wan (XLP)	p38 MAPK	Regulates expression of p38 MAPK	Modulates p38 MAPK in gastric cancer (GC) mouse model	[140]
Hulupolide-I	JNK/p38 MAPK	Induces expression of GADD45α and activates JNK/p38 MAPK pathway	Forms positive feedback loop between GADD45α and MAPK signaling, promoting apoptosis	[141]
Atractylodes Extract	MAPK signaling	Regulates MAPK pathway, increases caspase activity	Inhibits migration of gastric cancer AGS cells	[143]
Baicalin and Toosendanin	MAPK signaling	Modulates MAPK pathway	Exhibits anti-cancer properties	[144]
Lobetyol (from Lobelia chinensis)	MAPK signaling (ERK, JNK, p38)	Induces apoptosis and cell cycle arrest	Inhibits proliferation and induces apoptosis in MKN45 gastric cancer cells	[145]
CCMH (Compound Chinese Medicine)	PI3K/Akt, MAPK pathways	Regulates key proteins in PI3K/Akt and MAPK pathways	Inhibitscell proliferation, induces cell cycle arrest, and promotes apoptosis	[148]

MAPK inhibitors in gastric cancer: progress and challenges

Mitogen-activated protein kinase (MAPK) inhibitors, pivotal in targeting the signaling pathway implicated in numerous cancers, including gastric cancer, are classified based on their target pathways: ERK, P38, and JNK. Among these, P38 pathway inhibitors are the most thoroughly researched and are categorized into three main groups, each demonstrating a unique mechanism of action and molecular structure that underpin their inhibitory effects.

The first category includes pyridylimidazolyl aromatic heterocyclic compounds, with SB203580 being the prototypical and most extensively utilized inhibitor. These compounds primarily exert their inhibitory action by competing with ATP for binding sites, thus preventing the activation of the P38 MAPK pathway [149, 150]. The second group comprises non-aromatic heterocyclic compounds, including an array of chemical structures such as N, Nʹ-bisaryl urea, N, N-bisaryl urea, benzophenone, pyrazolone, indole amide, diamide, quinazoline, bis-pyrimidine, and pyridine-aminoquinazoline. These diverse compounds offer a broad spectrum of inhibitory potentials by targeting various components of the MAPK pathway [151–153]. The third category is constituted by natural products and herbal extracts, which have shown varying degrees of inhibition on the MAPK pathway [154]. The allure of natural inhibitors lies in their potential for lower toxicity and side effects, although their efficacy and safety profiles require rigorous validation through clinical trials. Despite promising results in non-clinical experiments, none of these inhibitors have yet been approved for clinical use due to concerns regarding their selective specificity, potential oncogenic effects, and toxic side effects, which pose significant challenges to their development as first-line clinical drugs.

Recent advancements have seen small molecule MAPK inhibitors progressing into clinical trials and preclinical studies, highlighting the evolving landscape of cancer therapeutics. Particularly, KRAS mutations, prevalent in gastrointestinal tumors, have been identified as critical targets for MAPK inhibitors, which have shown efficacy in inhibiting metastasis and angiogenesis in KRAS-mutant gastric cancers [155, 156]. Specifically, in the classical p38 MAPK pathway, MKK3 and MKK6, which activate p38 MAPK through dual phosphorylation, have emerged as promising targets for the development of novel inhibitors [157–159]. The exploration of these kinase targets underscores the ongoing efforts to refine and enhance the specificity and efficacy of MAPK inhibitors, aiming to mitigate the limitations associated with current compounds and to unlock new therapeutic avenues for cancer treatment [160, 161].

Targeted therapies in gastric cancer: MAPK and tyrosine kinase inhibitors

Tyrosine kinases are pivotal regulators of numerous downstream signaling pathways, including MAPK/PI3K/Akt and JAK/STAT, which are crucial in the progression and development of various cancers, notably gastric cancer. Inhibitors targeting a range of receptor tyrosine kinases have become increasingly prevalent in the therapeutic landscape for gastric cancer. Among these, Trastuzumab, a recombinant monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2), has garnered significant attention. HER2 is overexpressed in approximately 10% to 22% of gastric cancer cases, making it a valuable target for treatment [161–163]. Trastuzumab, especially when used in conjunction with lapatinib, has been effective in preventing HER3/EGFR reactivation, consequently achieving prolonged inhibition of ERK/Akt signaling [164]. This combination therapy has been shown to significantly inhibit HER3 expression, Akt phosphorylation, and ERK signaling, resulting in the substantial reduction of gastrointestinal tumors and enhanced patient survival [165], particularly in those with HER2-positive gastric cancer when paired with chemotherapy versus chemotherapy alone [166, 167]. As such, trastuzumab combined with platinum- and fluoropyrimidine-based chemotherapy remains the recommended first-line regimen for patients with HER2-positive gastric cancer [168, 169].

However, challenges remain in treating patients with untreated, HER2-negative, and surgically unresectable advanced tumors, as a complete and definitive regimen of targeted agents is yet to be established. While trastuzumab treatment marks a significant advancement in improving survival rates for patients with HER2-positive gastric cancer, issues such as intrinsic or acquired resistance to trastuzumab persist [170]. The activation of the PI3K pathway, which increases PDK1 expression in HER2 downstream signaling pathways (PI3K and MAPK pathways), and the subsequent activation of MAPK signaling pathways through direct phosphorylation of MAK1/2 by PDK1, underscore the potential of targeting PI3K or MAPK signaling pathways to enhance trastuzumab treatment sensitivity [171].

To fully ascertain the benefits of targeted drug therapy for patients with gastric cancer, more data from clinical and animal studies are needed. Additionally, the exploration of more immunotherapeutic targets in gastric cancer tissues is imperative. This expanding field of research holds great promise for improving treatment outcomes and patient survival, emphasizing the need for continued investigation into novel therapeutic strategies and the mechanisms underlying targeted therapies in gastric cancer (Table 6).

Table 6.

Role of targeted therapies in gastric cancer

Therapeutic drug	Target	Primary mechanism of action	Clinical efficacy	Limitations and challenges
Trastuzumab	HER2	Inhibits HER2 signaling, prevents HER3/EGFR reactivation, and maintains sustained ERK/Akt inhibition	Significantly improves survival rates and reduces tumor size in HER2-positive patients when combined with chemotherapy [165–167]	Ineffective for HER2-negative patients; may develop resistance [170]
Lapatinib	HER2/EGFR	Blocks HER2 and EGFR signaling, enhances HER3/EGFR inhibition	When combined with trastuzumab, significantly reduces HER3 expression and Akt/ERK phosphorylation levels [164]	Requires further research to support clinical application
PI3K/AKT Inhibitors	PI3K/AKT	Blocks PI3K signaling to reduce PDK1 expression, prevents MAPK and PI3K pathway activation	Potentially enhances trastuzumab sensitivity; currently under preclinical and clinical investigation	Limited clinical data; requires further exploration [171]
Immune Checkpoint Inhibitors	PD-1/PD-L1 and other immune targets	Enhances antitumor immune response	Shows potential to prolong survival in certain gastric cancer patients [additional studies required]	No comprehensive therapeutic regimen for gastric cancer; high demand for individualized treatment

Gastrointestinal microflora, MAPK signaling, and gastric cancer

Gastrointestinal microflora, though a minor component of the human microbiome, have immunoreactive properties, yet their role in human cancers remains largely unexplored. In gastric cancer, a high incidence of Candida is associated with the expression of pro-inflammatory immune pathways [172, 173]. The abundance of Helicobacter pylori increases in non-tumorous tissues, whereas the presence of Lactobacillus, Streptococcus, Bacteroides, Prevotella, and six other genera increases in tumor tissues. Helicobacter pylori infection significantly impacts the dysregulation of the gastric microbiome, potentially linked to this imbalance [174]. Helicobacter pylori and Lactobacillus show negative and positive correlations, respectively, with most differential metabolites in categories such as amino acids, carbohydrates, nucleosides, nucleotides, and glycerophospholipids, suggesting their roles in the degradation and synthesis of these differential metabolites [175, 176]. Successfully eradicating Helicobacter pylori might restore the gastric microbiome to a state similar to that of uninfected individuals, demonstrating beneficial effects on the gut microbiome [177]. The microbiome and its related metabolites are closely associated with carcinogenesis not only through inducing inflammation and immune dysregulation, leading to genetic instability but also by interfering with the pharmacokinetics of anticancer drugs [178].

The deactivation of the gastrointestinal microbiota can significantly compromise the integrity of the epithelial barrier [179]. Inflamed epithelial cells are exposed to the transcriptomic stress pathways induced by the microbiome associated with ulcerative colitis (UC), including the activation of EGR1, MAPK, and JAK/STAT signaling pathways, as well as the activation of AP-1 family transcription and FOSL transcription [180]. Contact between intestinal epithelial cells and certain commensal bacterial communities prompts the rapid production of reactive oxygen species (ROS) within the host cells. Enzymatically produced ROS have been demonstrated to act as a second messenger in many signal transduction pathways through the transient oxidation of sensor proteins with oxidant-sensitive thiol groups. Examples of redox-sensitive proteins include tyrosine phosphatases and focal adhesion kinase, as well as components involved in the activation of NF-kB, all of which serve as regulators in the MAPK pathway [181, 182].

Conclusion and perspective

Gastric cancer remains a significant challenge globally, particularly in developing nations where it exhibits high incidence rates. Notably, dietary modifications and the eradication of Helicobacter pylori have led to a marked reduction in gastric cancer cases in these regions. Despite these advancements, the therapeutic options for advanced and metastatic stages of gastric cancer are limited, offering modest improvements in patient survival. The mitogen-activated protein kinase (MAPK) pathway, known for its activation by a myriad of stimuli, plays a pivotal role in the intricate biological mechanisms governing gastric cancer’s progression and prognosis. This review has consolidated current research insights into the MAPK pathway’s involvement in gastric cancer, aiming to deepen our understanding of its risk factors. By pinpointing these factors, we strive to refine symptomatic treatments and develop comprehensive therapeutic strategies, ultimately enhancing survival outcomes for gastric cancer patients. This endeavor underscores the complexity and the pressing need for continued exploration within this domain, promising a future where more effective interventions are available to those battling this formidable disease.

Funding

Funded by the Anhui Province Scientific Research Staffing Plan Project, project approval number AH050668.

Declarations

Competing interests

All the authors report no relevant conflicts of interest for this article.