Role of myosin heavy chain 9 in gastrointestinal tumorigenesis: A comprehensive review

Abstract

Myosin heavy chain 9 (MYH9), a non-muscle myosin heavy chain protein, has been identified as a significant factor in gastrointestinal (GI) oncology, with its overexpression in various GI malignancies such as esophageal, gastric, and colorectal cancers being associated with poor prognosis and playing a role in tumor invasion and metastasis. This comprehensive review synthesizes the current body of knowledge regarding MYH9’s role in GI tumors, focusing on its molecular mechanisms, including its interaction with key signaling pathways like the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin axis, which suggests a role in cancer cell survival, proliferation, and epithelial-mesenchymal transition. The review also explores MYH9’s potential as a therapeutic target, with preclinical models demonstrating promising results in inhibiting tumor growth and enhancing chemosensitivity. The evidence suggests that MYH9 is a multifaceted protein with significant implications in GI tumor biology, warranting further research to elucidate its mechanisms of action and develop targeted therapies that could improve patient outcomes.

Key Words: Myosin heavy chain 9; Gastrointestinal tumors; Tumor invasion and metastasis; Prognostic biomarker; Therapeutic target; Chemoresistance; Phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling pathway

Core Tip: This review delves into the multifaceted role of myosin heavy chain 9 (MYH9) in gastrointestinal tumors. MYH9 is highly expressed in esophageal, gastric, and colorectal cancers, and is closely associated with tumor cell proliferation, invasion, metastasis, and chemoresistance. It also promotes tumor progression by regulating signaling pathways such as the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin axis. Moreover, MYH9 shows potential as a prognostic biomarker and therapeutic target, offering new directions for improving patient outcomes.

INTRODUCTION

Myosin heavy chain 9 (MYH9) encodes a non-muscle myosin II heavy chain protein, a member of the evolutionarily conserved myosin superfamily (Figure 1). It plays a crucial role in various cellular physiological processes, such as cell movement, division, and adhesion[1,2]. Historically, MYH9 was first identified through its association with inherited macrothrombocytopenias caused by MYH9 mutations, including May-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, and Sebastian syndrome - autosomal dominant disorders characterized by platelet abnormalities, leukocyte inclusions, and variable manifestations such as sensorineural hearing loss and nephritis[3].

Figure 1  Spatial structure of myosin heavy chain 9 protein.

In oncology, MYH9 has emerged as a dual-functional regulator with context-dependent roles. While predominantly acting as an oncogene in gastrointestinal (GI) tumors, it paradoxically exhibits tumor-suppressive activity in specific contexts. For instance, MYH9 loss in breast cancer correlates with increased genomic instability and metastatic potential[4], underscoring its functional complexity. In GI malignancies [esophageal, gastric, and colorectal cancers (CRCs)], MYH9 is consistently upregulated and associated with poor prognosis[5,6]. Mechanistically, MYH9 drives tumor progression through multiple pathways: (1) Enhancing epithelial-mesenchymal transition (EMT) via Snail/Slug stabilization[7]; (2) Activating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Wnt/β-catenin signaling to promote survival and stemness[8]; (3) Facilitating cytoskeletal remodeling through RhoA/ROCK-mediated actomyosin contraction, enabling invasion[9]; and (4) Synergizing with integrins to amplify growth factor receptor signaling[10].

Notably, the p-MYH9/ubiquitin-specific peptidase 22 (USP22)/hypoxia inducible factor-1 alpha (HIF-1α) axis exemplifies its role in therapeutic resistance. Phosphorylated MYH9 stabilizes HIF-1α through USP22-mediated deubiquitination, fostering cancer stemness and lenvatinib resistance in hepatocellular carcinoma (HCC)[11,12]. Recent studies have shown that MYH9 deficiency can promote colitis-related adenoma formation in the colon, likely due to impaired epithelial barrier function and increased inflammation. Additionally, MYH9 deletion has been linked to enhanced necroptosis, a form of programmed cell death that contributes to inflammation-driven carcinogenesis[13]. These findings highlight the complex role of MYH9 in GI tumorigenesis, suggesting that its function may vary depending on the cellular context. These findings position MYH9 as both a prognostic biomarker and a therapeutic target. Developing MYH9 inhibitors requires precision: Strategies targeting its ATPase activity (e.g., blebbistatin derivatives) or disrupting specific protein interactions (e.g., MYH9-integrin complexes) show promise while potentially sparing its physiological functions. Further elucidation of MYH9’s context-dependent mechanisms will advance targeted therapies for GI cancers.

STRUCTURE AND FUNCTION OF MYH9

Gene and protein structure of MYH9

The MYH9 gene, located on human chromosome 22q12.3, encodes the heavy chain of non-muscle myosin IIA, a key component of the actomyosin cytoskeleton. The MYH9 protein is a hexamer composed of a 226 kDa heavy chain and two pairs of light chains. Structurally, MYH9 comprises three major domains: The head, neck, and tail. The head domain, which harbors ATPase activity, is crucial for binding and hydrolyzing ATP to generate the energy required for myosin movement. This ATPase activity is fundamental for the motor function of myosin, enabling it to interact with actin filaments and produce contractile forces. The neck domain, often referred to as the lever arm, amplifies the power stroke generated by the head domain, enhancing the efficiency of myosin’s movement along actin filaments. The tail domain, on the other hand, is involved in dimerization and the formation of myosin filaments, which are essential for the organization and function of the actomyosin network[14-16]. Together, these domains confer MYH9 with its unique structural and functional properties, positioning it as a central player in various cellular processes[14].

Role of MYH9 in cell physiological processes

MYH9 is a critical regulator of several fundamental cell physiological processes, including cell movement, division, and adhesion[15]. In the context of cell movement, MYH9 interacts with actin to form actin fibers, which are essential for the assembly and remodeling of the cytoskeleton. This interaction enables cells to generate the necessary forces for migration and shape changes, facilitating processes such as wound healing and immune cell trafficking[17,18]. During cell division, MYH9 plays a pivotal role in the formation of contractile rings[19-22]. The contractile ring, composed of actin and myosin filaments, constricts to physically separate the dividing cell into two daughter cells. Proper formation and function of the contractile ring are crucial for ensuring accurate chromosome segregation and maintaining genomic stability. Additionally, MYH9 is involved in cell adhesion to the extracellular matrix (ECM), influencing cell morphology and function. By mediating the interaction between the cytoskeleton and the ECM, MYH9 helps maintain cell integrity and facilitates communication between the cell and its environment[23]. Collectively, these roles highlight the multifaceted importance of MYH9 in orchestrating essential cellular functions.

Expression pattern of MYH9 in normal tissues

MYH9 is widely expressed across various cell types in normal tissues, including epithelial cells, fibroblasts, and immune cells. The expression levels of MYH9 vary among different tissues, typically correlating with the degree of cell motility and division activity. For instance, in intestinal epithelial cells, MYH9 is highly expressed and actively participates in cell renewal and the maintenance of the mucosal barrier[24]. The dynamic nature of the intestinal epithelium, characterized by continuous cell turnover and the need for robust barrier function, necessitates the high expression and activity of MYH9 to support these processes[25]. Similarly, in tissues with high rates of cell division and migration, such as the skin and certain regions of the nervous system, MYH9 expression is elevated to meet the demands of these physiological activities[23,25]. This widespread and regulated expression pattern underscores the essential role of MYH9 in maintaining tissue homeostasis and function across diverse biological contexts.

MYH9 expression and its prognostic value in GI tumors

Expression level of MYH9 in esophageal, gastric, and colorectal cancers: Recent studies have consistently demonstrated that the expression level of MYH9 is significantly upregulated in esophageal, gastric, and colorectal cancers compared to adjacent normal tissues[23,26] (Figure 2). For instance, in esophageal squamous cell carcinoma, high MYH9 expression has been shown to correlate with deeper tumor invasion and lymph node metastasis[27]. This suggests that MYH9 may play a crucial role in the progression and metastatic potential of these cancers. Similarly, in gastric cancer, MYH9 expression levels are negatively correlated with tumor stage and patient survival. MYH9 has been shown to play a critical role in gastric cancer progression, with its expression significantly and positively correlated with tumor invasion depth, lymph node metastasis, distant metastasis, and tumor-node-metastasis stage. For example, studies have demonstrated that high MYH9 expression is associated with deeper tumor invasion and increased lymph node metastasis in gastric cancer patients, indicating its potential as a therapeutic target to inhibit tumor spread[28]. These findings suggest that targeting MYH9 could be particularly effective in advanced gastric cancer cases with high metastatic potential. High MYH9 expression in CRC is also closely associated with tumor recurrence and metastasis[29]. In early-stage CRC, MYH9 plays a critical role in tumor initiation and progression. Elevated MYH9 expression is often observed in precancerous lesions, such as adenomas, and is associated with increased cell proliferation and EMT. MYH9 promotes the transition from adenoma to carcinoma by enhancing cell survival and proliferation through interactions with the PI3K/AKT/mechanistic target of rapamycin (mTOR) and Wnt/β-catenin pathways. Additionally, MYH9 disrupts epithelial barrier function, facilitating tumor cell invasion into the submucosa. These findings highlight MYH9’s importance in early CRC development, suggesting its potential as a target for early intervention. These findings collectively indicate that MYH9 may serve as a potential biomarker for the aggressiveness and metastatic potential of GI malignancies.

Figure 2 Expression of myosin heavy chain 9 in esophageal cancer, gastric cancer, and colorectal cancer. MYH9: Myosin heavy chain 9.

Relationship between MYH9 expression and patient prognosis: The prognostic significance of MYH9 expression in GI cancers has been extensively studied. In esophageal cancer patients, elevated MYH9 expression is associated with shorter disease-free survival and overall survival[30]. This suggests that MYH9 may be a valuable predictor of poor prognosis in this patient population. In gastric cancer, high MYH9 expression is linked to lower 5-year survival rates[31]. Similarly, in CRC, high MYH9 expression is associated with higher recurrence rates and shorter disease-free survival[1]. These studies collectively highlight the potential of MYH9 as a prognostic biomarker in GI cancers, providing valuable insights into patient outcomes and guiding clinical decision-making.

Potential of MYH9 as a prognostic biomarker: Given the strong correlation between MYH9 expression and tumor invasion, metastasis, and patient prognosis in GI cancers, its potential as a prognostic biomarker has garnered significant attention. Several studies have attempted to integrate MYH9 expression into prognostic models to enhance the accuracy of predicting patient outcomes[32,33]. For example, a study on gastric cancer patients demonstrated that incorporating MYH9 expression levels into a prognostic model could more accurately predict patient survival[34]. This suggests that MYH9 may serve as an important component in comprehensive prognostic assessments for GI cancers. However, further validation studies are still needed to fully establish the clinical utility of MYH9 as a prognostic biomarker. Future research should focus on large-scale, multi-center studies to confirm the prognostic value of MYH9 and explore its potential as a therapeutic target in GI malignancies. Furthermore, rigorous prospective, multi-institutional collaborative studies are imperative to validate these findings and elucidate the translational implications of MYH9 in clinical oncology.

Molecular mechanisms of MYH9 in GI tumorigenesis and development

MYH9 and cell proliferation: MYH9 plays a crucial role in the proliferation of GI tumor cells. Accumulating evidence indicates that elevated MYH9 expression can significantly enhance the proliferation rate of tumor cells, whereas inhibiting MYH9 expression exerts a suppressive effect on cell proliferation. For instance, in esophageal cancer cells, silencing MYH9 expression through RNA interference techniques has been shown to markedly reduce cell proliferation rates. This suggests that MYH9 may act as a key regulator of cell cycle progression. Specifically, high MYH9 expression levels can facilitate the transition of cells from the G1 phase to the S phase, thereby accelerating cell cycle progression and promoting cell proliferation[35]. This mechanism underscores the potential of MYH9 as a therapeutic target for inhibiting tumor growth.

MYH9 and tumor invasion and metastasis: MYH9 is also a key player in the invasion and metastasis of GI tumors. Research has consistently demonstrated that high MYH9 expression is associated with enhanced tumor cell invasion and metastatic potential[36]. Conversely, inhibiting MYH9 expression can significantly attenuate these processes. For example, in gastric cancer cells, silencing MYH9 expression has been shown to reduce cell invasion and migration capabilities[37]. This effect is likely mediated through the regulation of cytoskeleton remodeling and cell adhesion to the ECM. MYH9, as a component of the actomyosin network, can influence the dynamics of actin filaments and focal adhesions, thereby modulating cell motility and adhesion. High MYH9 expression increases cell motility and enhances cell-ECM interactions, facilitating tumor cell dissemination and metastasis[1]. These findings highlight the importance of MYH9 in the metastatic cascade and suggest that targeting MYH9 could be a promising strategy to inhibit tumor spread.

MYH9 and EMT: EMT is a critical process in tumor invasion and metastasis, and MYH9 has been shown to play a significant role in this process. EMT is characterized by the loss of epithelial markers (e.g., E-cadherin) and the gain of mesenchymal markers (e.g., N-cadherin and vimentin), which endows cells with enhanced migratory and invasive capabilities. Studies have demonstrated that high MYH9 expression promotes EMT, while inhibiting MYH9 expression suppresses this process[1]. For example, in CRC cells, silencing MYH9 expression significantly reduced the expression of EMT-related markers such as N-cadherin and vimentin. Mechanistically, MYH9 may promote EMT by modulating EMT-related signaling pathways. High MYH9 expression has been shown to activate the transforming growth factor-beta (TGF-β) signaling pathway, a key driver of EMT, thereby facilitating the transition from an epithelial to a mesenchymal phenotype[38]. This highlights the potential of MYH9 as a therapeutic target to inhibit EMT and, consequently, tumor metastasis.

MYH9 and tumor stem cells: Tumor stem cells (TSCs) are a subpopulation of cancer cells with self-renewal and differentiation capabilities, and they are considered a major cause of tumor recurrence and metastasis[39]. MYH9 has been implicated in the regulation of TSC properties. Studies have shown that high MYH9 expression promotes the self-renewal and differentiation of TSCs, while inhibiting MYH9 expression suppresses these processes[40]. For example, in gastric cancer stem cells, silencing MYH9 expression significantly reduced the self-renewal capacity and differentiation potential of TSCs[41]. This suggests that MYH9 may contribute to the maintenance of TSCs by modulating signaling pathways that support their stemness properties. Targeting MYH9 could potentially deplete TSCs, thereby reducing the risk of tumor recurrence and improving patient outcomes[42]. Further research is needed to elucidate the specific mechanisms by which MYH9 regulates TSCs and to explore its potential as a therapeutic target in this context.

Interaction of MYH9 with GI tumor-related signaling pathways

MYH9 and PI3K/AKT/mTOR signaling pathway: The PI3K/AKT/mTOR signaling pathway is a critical regulator of tumor cell survival, proliferation, and metabolism[43,44]. Emerging evidence has highlighted the role of MYH9 in activating this pathway, thereby contributing to GI tumorigenesis and development. For instance, in esophageal cancer, high MYH9 expression is closely associated with the activation of the PI3K/AKT/mTOR pathway, which in turn correlates with poor patient prognosis[14,45]. Similarly, in CRC, MYH9 has been shown to promote tumor cell proliferation and survival by activating the PI3K/AKT/mTOR pathway[46]. Mechanistically, MYH9 may interact with upstream regulators or downstream effectors of this pathway, enhancing its activity and driving tumor progression[47,48]. These findings underscore the potential of targeting the MYH9-PI3K/AKT/mTOR axis as a therapeutic strategy for GI cancers (Figure 3).

Figure 3 Phosphatidylinositol 3-kinase/protein kinase B pathway is involved in cell growth, differentiation, and tumorigenesis. When the ligand binds to the membrane receptor, the receptor and myosin heavy chain 9 activate phosphatidylinositol 3-kinase, which then catalyzes the formation of phosphatidylinositol-3-phosphate from phosphatidylinositol 4,5-biphosphate on the inner surface of the membrane. As the second messenger, phosphatidylinositol-3-phosphate further activates protein kinase B. Protein kinase B can activate the downstream mammalian target of rapamycin pathway, which can phosphorylate and activate S6 kinase 1 and 4E-binding protein, and finally participate in gene expression. PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin. MYH9: Myosin heavy chain 9; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; PIP2: Phosphatidylinositol 4,5-biphosphate; PIP3: Phosphatidylinositol-3-phosphate; S6K1: S6 kinase 1; 4EBP: 4E-binding protein; PTEN: Phosphatase and tensin homolog.

MYH9 and mitogen-activated protein kinase signaling pathway: The mitogen-activated protein kinase (MAPK) signaling pathway is a key regulator of cell proliferation, differentiation, and apoptosis. MYH9 has been implicated in the activation of this pathway, thereby promoting the development of GI tumors[1]. In head and neck cancer, MYH9 regulates intracellular reactive oxygen species levels and enhances tumor cell invasion and radioresistance by activating the MAPK/nuclear factor erythroid-derived 2/glutamate-cysteine ligase catalytic subunit pathway[41]. Additionally, in breast cancer, MYH9 promotes tumor cell invasion and metastasis through the activation of the MAPK pathway[49]. These studies suggest that MYH9-mediated activation of the MAPK pathway plays a significant role in tumor progression. Targeting MYH9 or its downstream effectors in the MAPK pathway could potentially inhibit tumor invasion and improve patient outcomes (Figure 4).

Figure 4 Myosin heavy chain 9 activates pan-mitogen-activated protein kinase signaling molecules, including extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase. This activation leads to the induction of nuclear factor erythroid-derived 2 transcriptional activity, the upregulation of the antioxidant enzymes, and the reduction of cellular reactive oxygen species levels. The antioxidant enzyme, such as glutamate-cysteine ligase catalytic subunit, further confers cell invasion and radioresistance, resulting in aggressive cancer and poor prognosis. MYH9: Myosin heavy chain 9; MAPK: Mitogen-activated protein kinases; Nrf2: Nuclear factor erythroid-derived 2; ARE: Antioxidant response element; ROS: Reactive oxygen species; GCLC: Glutamate-cysteine ligase catalytic subunit; GCLM: Glutamate-cysteine ligase modifier subunit.

MYH9 and other related signaling pathways: Beyond the PI3K/AKT/mTOR and MAPK pathways, MYH9 interacts with a variety of other signaling pathways to drive GI tumorigenesis and development. In HCC, MYH9 may activates the TGF-β signaling pathway and promotes tumor cell invasion and metastasis by interacting with the X protein encoded by the hepatitis B virus[50,51]. Furthermore, in esophageal cancer, MYH9 activates the Wnt/β-catenin signaling pathway, thereby enhancing tumor cell proliferation and survival[52] (Figure 5). These findings highlight the multifaceted role of MYH9 in tumor biology, suggesting that it functions as a central hub in a complex signaling network. Future research should focus on elucidating the specific mechanisms by which MYH9 interacts with these pathways and identifying potential therapeutic targets within this network.

Figure 5 Myosin heavy chain 9 activates the Wnt/β-catenin signaling pathway to enhance the proliferation and survival of cancer cells. Myosin heavy chain 9 activates the transforming growth factor-beta signaling pathway and promotes tumor cell invasion and metastasis by interacting with the X protein encoded by the hepatitis B virus. MYH9: Myosin heavy chain 9; HBV: Hepatitis B virus; TGF-β: Transforming growth factor-beta; JNK: C-Jun N-terminal kinase.

Progress of MYH9 as a therapeutic target for GI tumors

Targeted therapeutic strategies against MYH9: Given the pivotal role of MYH9 in GI tumorigenesis and progression, targeted therapeutic strategies against MYH9 have garnered significant attention in recent years. MYH9 is involved in multiple cellular processes that drive tumor development, including cell proliferation, invasion, and metastasis. Therefore, inhibiting MYH9 activity or expression represents a promising approach for cancer treatment. Currently, several therapeutic agents targeting MYH9 are under investigation, encompassing both small molecule inhibitors and monoclonal antibodies.

Recent advances have identified specific and effective MYH9-targeted therapies, including small molecule inhibitors and monoclonal antibodies. For example, blebbistatin, a small molecule inhibitor, selectively targets MYH9’s ATPase activity, disrupting its motor function and inhibiting tumor cell motility and invasion[53]. Additionally, monoclonal antibodies against MYH9, such as 4H12, have shown promise in preclinical studies by blocking MYH9’s interaction with downstream signaling pathways, thereby suppressing tumor growth and metastasis[54]. These targeted therapies offer potential for precise intervention in MYH9-driven GI cancers[14,55,56] (Table 1).

Table 1 Summary of potential therapeutic drugs targeting myosin heavy chain 9 and their characteristics.

Drug name	Type	Characteristics	Mechanism of action	Indication	Explanation
Blebbistatin	Small-molecule reference	High selectivity for myosin II ATPase	Binds to the ATP-binding domain of MYH9, inhibiting its function	Breast cancer, glioblastoma multiforme	As a classic myosin II inhibitor, blebbistatin inhibits MYH9 function by binding to its ATPase active domain. Research shows that it can significantly reduce tumor cell migration and metastasis in breast cancer models, but structural optimization is needed for clinical application due to phototoxicity and toxicity issues[14]
ML-7	Small-molecule reference	Myosin light chain kinase inhibitor	Inhibits MLCK, indirectly regulating MYH9 phosphorylation	Colorectal cancer, pancreatic cancer	This drug indirectly regulates MYH9 phosphorylation by inhibiting MLCK, reducing tumor cell invasiveness. In pancreatic cancer models, ML-7 enhances chemotherapeutic sensitivity when used with gemcitabine[55]
CX-4945	Small-molecule reference	Targeting protein kinase	Inhibits CK2, regulating MYH9 phosphorylation and HIF-1α expression	HCC	CX-4945 inhibits phosphorylation of MYH9 at Ser1943, HIF-1α expression, and its transcriptional activity, thus suppressing tumor stemness of LR cells and enhancing lenvatinib sensitivity in HCC LR cells[56]

MYH9: Myosin heavy chain 9; MLCK: Myosin light chain kinase; HIF-1α: Hypoxia inducible factor-1 alpha; HCC: Hepatocellular carcinoma.

Preclinical studies of MYH9-targeted therapy: Numerous preclinical studies have demonstrated the efficacy of MYH9-targeted therapies in inhibiting GI tumor growth and enhancing the sensitivity of cancer cells to chemotherapy. In esophageal cancer, silencing MYH9 expression using RNA interference techniques has been shown to significantly suppress tumor cell proliferation and invasion. This inhibition of MYH9 not only reduces the intrinsic growth capacity of tumor cells but also enhances their sensitivity to chemotherapeutic agents such as cisplatin and 5-fluorouracil. Similarly, in CRC, preclinical studies have revealed that inhibiting MYH9 expression can significantly reduce tumor cell proliferation and survival[1]. These findings suggest that MYH9-targeted therapies may have broad applications in the treatment of GI cancers, potentially improving patient outcomes by enhancing the efficacy of existing treatments.

Potential challenges of MYH9-targeted therapy: Despite the promising results observed in preclinical studies, several challenges remain in the development and application of MYH9-targeted therapies. First, MYH9 is expressed in various normal tissues, raising concerns about potential off-target effects and toxicity. Since MYH9 plays essential roles in normal cellular functions such as cell adhesion and cytokinesis, inhibiting its activity may lead to adverse effects on healthy tissues. Therefore, it is crucial to develop highly specific inhibitors or antibodies that can selectively target MYH9 in tumor cells while minimizing toxicity to normal cells.

Second, tumor cells may develop resistance to MYH9-targeted therapies by compensating through alternative signaling pathways[52]. For example, tumor cells may upregulate other myosin family members or activate compensatory pathways to bypass the inhibition of MYH9[48]. This adaptive response can limit the long-term efficacy of MYH9-targeted therapies. To address this challenge, combination therapies that target multiple pathways simultaneously may be necessary. By inhibiting both MYH9 and its compensatory pathways, it may be possible to achieve more durable therapeutic responses and overcome resistance mechanisms. One significant challenge in MYH9-targeted therapy is the potential for tumor cells to bypass MYH9 inhibition, leading to therapeutic resistance. For instance, tumor cells may upregulate other myosin family members or activate compensatory pathways, such as the RhoA/ROCK or MAPK signaling pathways, to maintain cell motility and survival[57]. This adaptive response highlights the need for combination therapies that simultaneously target MYH9 and its compensatory mechanisms to achieve durable therapeutic effects.

In conclusion, while MYH9-targeted therapies show promise in preclinical studies, their development and application face significant challenges. The widespread expression of MYH9 in normal tissues raises concerns about off-target effects and toxicity, necessitating the development of highly specific inhibitors or antibodies that can selectively target MYH9 in tumor cells. Additionally, tumor cells may develop resistance to MYH9-targeted therapies through compensatory mechanisms involving alternative signaling pathways, such as upregulation of other myosin family members or activation of pathways like RhoA/ROCK or MAPK. To address these challenges, combination therapies targeting both MYH9 and its compensatory pathways may be required to achieve durable therapeutic responses and overcome resistance mechanisms.

OUTLOOK

Summary of the importance of MYH9 in GI tumors

In summary, MYH9 emerges as a critical player in the occurrence, development, and metastasis of GI tumors. Its overexpression is strongly associated with tumor cell proliferation, invasion, metastasis, and resistance to chemotherapy. MYH9 promotes GI tumorigenesis and development through interactions with multiple signaling pathways, including PI3K/AKT/mTOR, MAPK, Wnt/β-catenin, and TGF-β pathways. These interactions drive various oncogenic processes, such as cell cycle progression, EMT, and cancer stemness. Therefore, MYH9 not only serves as a prognostic biomarker for predicting patient outcomes but also holds potential as a therapeutic target for GI cancers.

Future research directions

Despite the growing body of evidence highlighting the role of MYH9 in GI tumors, several key questions remain to be addressed. First, the specific mechanisms by which MYH9 contributes to tumorigenesis and progression in different GI cancers are not fully elucidated. For instance, the precise role of MYH9 in the early stages of CRC and its interaction with other genes and signaling pathways warrant further investigation. Additionally, the potential compensatory mechanisms that tumor cells may employ to bypass MYH9 inhibition need to be explored to address therapeutic resistance. Further research is needed to fully elucidate the specific mechanisms by which MYH9 contributes to tumorigenesis in different GI cancers. Additionally, the role of MYH9 in modulating the tumor microenvironment and its interaction with signaling pathways such as Wnt/β-catenin and TGF-β remains to be explored. Understanding these interactions could provide new insights into MYH9’s dual role in tumor suppression and promotion. Moreover, identifying novel MYH9-interacting proteins and elucidating their functional significance in tumor biology is crucial. For example, recent studies have identified MYH9 interactions with proteins involved in cytoskeletal regulation, cell adhesion, and signal transduction, which may reveal new therapeutic targets[58]. Moreover, the development of more specific and effective MYH9-targeted therapies, and the optimization of preclinical models to better reflect human disease, are essential steps toward translating these findings into clinical practice.

Prospects of MYH9-targeted therapy

Given the multifaceted role of MYH9 in GI tumors, targeting MYH9 represents a promising therapeutic strategy. Future studies need to delve deeper into the mechanisms underlying MYH9’s oncogenic functions and develop more effective targeted therapeutic agents. For example, small molecule inhibitors and monoclonal antibodies against MYH9 are currently under investigation, but their specificity and efficacy need to be enhanced. For instance, blebbistatin, a well-known small molecule, inhibits MYH9 function by binding to its ATPase active domain, thereby reducing tumor cell migration and metastasis. ML-7 indirectly regulates MYH9 phosphorylation by inhibiting myosin light chain kinase, decreasing tumor cell invasiveness[59]. CX-4945, another small molecule inhibitor, suppresses tumor cell proliferation and migration by interfering with MYH9-related signaling pathways[60]. Monoclonal antibodies targeting MYH9 are also in development, aiming to block its function or mark it for immune system targeting. These drugs have shown promise in various cancer models but remain under study, needing more optimization and validation for clinical use. Furthermore, combining MYH9-targeted therapies with other treatment modalities, such as chemotherapy, radiotherapy, and immunotherapy, may synergistically improve therapeutic outcomes[14,57]. Preclinical studies have shown that inhibiting MYH9 can enhance the sensitivity of cancer cells to chemotherapeutic agents, suggesting that combination therapies could be particularly effective[61]. Additionally, exploring the potential of natural compounds, such as palmatine, which has been shown to downregulate MYH9 and inhibit tumor progression, may offer novel therapeutic avenues[62]. In conclusion, while MYH9-targeted therapies hold significant promise, a comprehensive and multidisciplinary approach is needed to fully realize their clinical potential and improve patient outcomes in GI cancers.

CONCLUSION

MYH9 is a multifaceted protein with significant implications in GI tumor biology. Its overexpression is associated with poor prognosis and enhanced tumor invasion and metastasis. MYH9’s interactions with key signaling pathways, such as the PI3K/AKT/mTOR axis, further contribute to tumor progression. Targeting MYH9 has shown promise in preclinical models, warranting further research to develop effective therapies. Future studies should focus on elucidating MYH9’s mechanisms of action and optimizing targeted therapies to improve patient outcomes.

In particular, the role of MYH9 in modulating the tumor microenvironment and its crosstalk with other signaling pathways, such as Wnt/β-catenin and TGF-β, warrant further investigation. Additionally, the development of specific inhibitors targeting MYH9 or its downstream effectors, such as the p-MYH9/USP22/HIF-1α axis in HCC, may provide novel therapeutic opportunities. Moreover, combining MYH9-targeted therapies with other treatment modalities, such as chemotherapy, radiotherapy, or immunotherapy, may enhance therapeutic efficacy and overcome resistance mechanisms. For example, inhibiting MYH9 in combination with PI3K/AKT/mTOR pathway inhibitors or immune checkpoint blockers could synergistically suppress tumor growth and metastasis[63]. Future studies should focus on optimizing these combination strategies to improve patient outcomes in GI cancers. Overall, a comprehensive understanding of MYH9’s functions and interactions in GI tumors is essential for translating these insights into clinical applications and improving patient outcomes.