Zonula occludens proteins and their impact on the cancer microenvironment

ZO proteins and their impact on TME

Article information

Kosin Med J. 2024;39(4):246-253

Publication date (electronic) : 2024 December 6

doi : https://doi.org/10.7180/kmj.24.136

Min-Hye Kim ¹

, Hee-Jae Cha^,²

¹Department of Biomedical Sciences, Dong-A University College of Medicine, Busan, Korea

²Department of Parasitology and Genetics, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea

Corresponding Author: Hee-Jae Cha, PhD Department of Parasitology and Genetics, Kosin University Gospel Hospital, Kosin University College of Medicine, 262 Gamcheon-ro, Seo-gu, Busan 49267, Korea Tel: +82-51-990-6428 Fax: +82-51-990-3081 E-mail: hcha@kosin.ac.kr

Received 2024 August 29; Revised 2024 September 19; Accepted 2024 September 25.

Abstract

Zonula occludens (ZO) proteins serve as scaffolding proteins that provide structural support at cell junctions and the cytoplasmic surface, acting as bridges between integral membrane proteins and the cytoskeleton. In addition to their structural functions, they also regulate cell growth and proliferation. Recent studies have shown that ZO proteins are involved in various diseases, including cancer. Specifically, ZO proteins influence the growth and development of cancer cells in the tumor microenvironment. These proteins perform various functions in the tumor microenvironment through processes such as angiogenesis, inflammatory responses, epithelial-mesenchymal transition, and interactions with mesenchymal stem cells. The mechanisms of these actions may vary depending on the type of cancer and environmental conditions. Ongoing research explores several signaling pathways involving ZO proteins. These insights suggest that new therapeutic approaches may be considered to slow down cancer growth and development within the tumor microenvironment. Despite continuing research on the cellular and in vivo roles of ZO proteins, the current understanding of how these signaling mechanisms function within the tumor microenvironment in vivo remains limited. In this review, we introduce the characteristics and regulatory mechanisms of ZO proteins in the cancer microenvironment, explore their potential to suppress cancer cell environments, and examine their roles in vivo.

Keywords: Animals; Biological phenomena; Neoplasms; Tumor microenvironment; Zonula occludens

Introduction

Tight junctions, adherens junctions, and desmosomes serve as important protective barriers in multicellular organisms and are present in epithelial and endothelial cells. Tight junctions play a crucial role in regulating communication and transport between cells, involving proteins such as claudins, occludins, cingulin, protein associated with LIN7 1, multiple PDZ domain (postsynaptic density protein of 95 kDa, Drosophila disc large tumor suppressor, and zonula occludens [ZO]-1 protein) crumbs cell polarity complex component, and ZO-1, ZO-2, and ZO-3. ZO proteins are key to the formation of tight junctions between cells, interacting directly with the PDZ domain and the C-terminus of claudins. They also regulate various signaling pathways in cancer cells [1]. Representative cancer types associated with ZO proteins include breast cancer [2], liver cancer [3], colon cancer [4], bladder cancer [5], non-small cell lung cancer [6] and gastrointestinal stromal tumors [7]. The expression pattern of ZO proteins varies depending on the type of cancer, demonstrating their influence on various malignancies. Recent studies have shown that ZO proteins play a critical role not only in cancer itself but also in the cancer microenvironment. The cancer microenvironment refers to the tissues and proteins surrounding cancer cells, including tumor cells, tumor stromal cells, endothelial cells, immune cells, collagen, and the extracellular matrix. Cancer cells, at the center of the cancer microenvironment, regulate the functions of these cellular and non-cellular components through a complex signaling network, thereby exploiting non-malignant cells to benefit tumor growth [8]. Furthermore, in the cancer microenvironment, ZO proteins exhibit cancer-specific properties. For example, they have been reported to suppress epithelial-mesenchymal transition (EMT) and influence the cancer microenvironment in lung cancer [9], while promoting tumor angiogenesis in breast cancer [10]. These findings suggest that ZO proteins significantly impact the cancer microenvironment. However, further research is needed to fully understand the effects of ZO proteins on other proteins and signaling pathways within the cancer microenvironment. This review therefore aims to explore the relevance of ZO proteins in the cancer microenvironment and examine their mechanisms of action.

ZO proteins in the cancer microenvironment

ZO proteins are located between transmembrane proteins and the actin cytoskeleton, where they form structural support, regulate cell adhesion, and bind to actin, occludin, and claudin. However, recent studies have reported that ZO proteins are involved not only in several diseases but also in the cancer microenvironment [11]. Therefore, it is necessary to explore the various mechanisms by which ZO proteins act in cancer, beyond their previously known roles.

Cancer forms a complex ecosystem composed of tumor cells and numerous normal tissue cells, collectively known as the cancer microenvironment. This environment includes various immune cells, cancer-associated fibroblasts, endothelial cells, perivascular cells, and other tissue cells. These cells play crucial roles in tumor development, and the composition and function of the cancer microenvironment vary depending on the tumor's location, the characteristics and stage of the cancer cells, and patient-specific factors. Various cells within the cancer microenvironment can either suppress or support tumor growth [12]. The expression of ZO proteins can influence factors related to the cancer microenvironment and vice versa. A recent study reported that knockout of tight junction protein 1 (Tjp1) and tight junction protein 2 (Tjp2), which are ZO protein genes, significantly increased cell proliferation, migration, invasion, tumor growth, and metastatic potential. Next-generation sequencing analysis revealed that genes related to the cell cycle, cell migration, angiogenesis, and cell-cell adhesion were significantly affected [13].

In the cancer microenvironments studied thus far, ZO protein-related factors include angiogenesis, inflammatory response, EMT, and mesenchymal stem cells. Angiogenesis, the process by which new blood vessels form from existing ones, is essential for the growth and metastasis of cancer cells. The inflammatory response refers to the body's reaction to tissue damage or antigen invasion, and chronic inflammation contributes to cancer development. EMT is the process by which epithelial cells lose their adhesion to neighboring cells, gain mobility, and acquire invasiveness, transforming into mesenchymal cells. Mesenchymal stem cells are multipotent stromal cells that can differentiate into various cell types and play a significant role in cancer cell metastasis and invasion. In the cancer microenvironment, these cells can differentiate into stromal cells, such as cancer-associated fibroblasts, and influence tumor progression [14-16]. Therefore, this discussion will delve into the role of ZO proteins in these cancer microenvironment factors.

1. Angiogenesis

Recent studies have reported that ZO proteins are involved in angiogenesis [10]. Angiogenesis is the process by which new blood vessels are formed from existing ones, and it is important for growth and development, wound healing, and granulation tissue formation. However, in cancer, tumor cells may utilize surrounding blood vessels to receive nutrients and metastasize, or they may be involved in the formation of new blood vessels, contributing to the malignancy of the tumor. Growth factors such as vascular endothelial growth factor, fibroblast growth factor (FGF), and epidermal growth factor are essential for angiogenesis. Among these, FGF has been reported to be associated with ZO proteins. In one study, human dermal microvascular endothelial cells with suppressed ZO-1 expression were injected subcutaneously into C57BL/6 mice to create a Matrigel plug model. It was observed that suppression of ZO-1 led to decreased angiogenesis along with a reduction in FGF expression [17]. Additionally, ZO-1 has been reported to indirectly promote angiogenesis in breast and lung cancer by regulating cytokines such as CXC motif chemokine ligand 8 and interleukin (IL)-8 [10]. These findings suggest that ZO proteins in the cancer microenvironment regulate peripheral factors such as growth factors and cytokines or participate in mechanisms that induce angiogenesis in cancer cells, thereby influencing the growth and invasion of tumors.

2. Inflammation response

Inflammatory responses are protective mechanisms of innate immunity, mediated by nonspecific immune cells, blood vessels, and inflammatory mediators. They play a crucial role in protecting cells and preventing tissue damage. Diseases related to inflammation include inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease, and numerous studies have shown that these diseases are linked to ZO proteins [18-22]. Recent studies highlighted the influence of ZO proteins on inflammatory responses in the cancer cell environment. For instance, research has confirmed the association of ZO-1 with carcinogenesis and tumorigenesis in hepatocellular carcinoma (HCC). It was observed for the first time that ZO-1 levels were significantly elevated in HCC patients and positively correlated with inflammatory markers, suggesting that inflammatory responses may elevate plasma ZO-1 concentrations. This finding indicates that ZO-1 could serve as a potential biomarker [23]. In non-small cell lung cancer, which accounts for 80%–85% of lung cancer cases, an association with ZO proteins has also been reported. A previous study demonstrated that the nuclear content of ZO-1 influences the regulation of various inflammatory chemokines. The study further showed that CD8+ cytotoxic T cells and FOXP3+ immunosuppressive regulatory T cells, which are abundant in lung cancer, were correlated with the nuclear expression of ZO-1. This suggests that ZO-1 may be involved in recruiting immune cells to the nucleus of cancer cells by altering tumor cell secretions, thereby promoting tumor progression [6]. Moreover, the importance of ZO proteins has been confirmed in other lung cancers. In studies of lung adenocarcinoma and lung squamous cell carcinoma, it was found that the expression of ZO-1 and ZO-2 was low. When Calu-1 cells (human lung squamous cell carcinoma cells) with reduced ZO-1 or ZO-2 expression were co-cultured with M0 macrophages, M2-like polarization was induced. Conversely, when M0 THP-1 cells (human monocytic cells) were co-cultured with cells expressing ZO-1 or ZO-2, M2 differentiation was significantly reduced. This suggests that abnormal expression of ZO-1 and ZO-2 may play a role in lung cancer development and the regulation of the cancer microenvironment [9]. These findings suggest that ZO proteins are closely involved in inflammatory response within the cancer microenvironment. However, additional research is needed to better understand the mechanisms and roles of ZO proteins in inflammatory responses occurring in the environment surrounding cancer cells.

3. Epithelial-mesenchymal transition

ZO proteins have also been reported to be associated with EMT in the cancer cell environment. EMT is an invasive process that occurs in many types of cancer, characterized by increased cell mobility as epithelial cells acquire mesenchymal cell traits, leading to cancer metastasis. The first step of EMT involves the disassembly of cell-cell contacts in epithelial cells, which are connected by tight junctions, adherens junctions, and desmosomes. Among these, ZO-1 plays a critical role in regulating tight junctions and adherens junctions by influencing cytoskeletal assembly and dynamics. Based on this, it has been reported that RNA binding motif protein 38 promotes EMT by regulating the transcriptional expression of ZO-1 in breast cancer [24]. Another study found that the overexpression of insulin-like growth factor I receptor (IGF-IR) during primary breast cancer development affected ZO-1 overexpression as part of the mechanism that regulates cell-to-cell adhesion via E-cadherin. This suggests that ZO-1 is involved in strengthening the connection between the E-cadherin complex and the actin cytoskeleton through activated IGF-IR, thereby regulating cell-to-cell adhesion [25]. Furthermore, the association between ZO proteins and EMT has also been reported in melanoma cells. Although ZO-1 expression is generally reduced in most cancers, leading to increased cancer cell motility, ZO-1 expression is elevated in melanoma cells. In these cells, ZO-1 is highly co-expressed with N-cadherin, a mesenchymal marker, promoting melanoma carcinogenesis [26]. These findings confirm the critical role of ZO proteins in EMT within the cancer microenvironment and suggest that this role should be investigated across a broader range of cancer types.

4. Mesenchymal stem cells

Mesenchymal stem cells are multipotent stem cells with the ability to differentiate into osteoblasts, chondrocytes, and adipocytes. These cells promote tumor growth in various types of cancer. Additionally, mesenchymal stem cells have been observed to migrate from the bone marrow to the breast cancer microenvironment, where they differentiate into stromal cells such as fibroblasts. Based on this, a study was conducted to elucidate the intrinsic mechanism by which bone marrow-derived mesenchymal stem cells aggregate in the breast cancer microenvironment, with a focus on the role of ZO-1. The research team confirmed that ZO-1 plays a crucial role in mediating the collective migration of mesenchymal stem cells in breast cancer cells and in converting transforming growth factor-β. They discovered that ZO-1 aggregates in adherens junctions at the contact points between mesenchymal stem cells. Additionally, it was found that ZO-1 cooperates with α-catenin to regulate adherens junctions through the SRC homology 3 and guanylate kinase 1 domains of the ZO-1 protein. This mechanism suggests that ZO-1 can influence the migration of mesenchymal stem cells [27]. This study is the first to report the direct involvement of ZO proteins in mesenchymal stem cells within the cancer microenvironment. Until recently, only indirect influences of ZO proteins on mesenchymal stem cells in damaged human pulmonary microvascular endothelial cells had been studied [28]. Therefore, further investigation into the role of ZO proteins in mesenchymal stem cells and their new functions in the cancer microenvironment is warranted.

5. Other factors and ZO protein associations

ZO proteins have also been shown to be associated with other factors present in the tumor microenvironment. One such factor is glucocorticoids. Glucocorticoids play an important role in central nervous system disorders associated with an impaired blood-brain barrier (BBB), such as edema, brain tumors, and multiple sclerosis. In a study testing the hypothesis that dexamethasone (DEX) treatment enhances the recovery of a BBB model composed of mouse brain endothelial cells in vitro, it was confirmed that ZO-1 expression increased during DEX treatment and recovery, suggesting a structural role for ZO-1 in BBB recovery [29]. Additionally, transcription factors can influence the tumor microenvironment. ZO-1-associated nucleic acid-binding protein (ZONAB), a transcription factor, promotes cell proliferation and the expression of proliferating cell nuclear antigen by shuttling between tight junctions and the nucleus. ZONAB has been reported to be a key component of the transcriptional network that senses epithelial cell density and regulates the transition between proliferation and differentiation [30]. One study confirmed that overexpression of ZONAB increased cell density in mature monolayers, while loss of ZONAB or overexpression of ZO-1 decreased cell density [31]. Furthermore, it was revealed that ZONAB interacts with cyclin-dependent kinase 4 (CDK4), accumulates in the nucleus, and promotes cell proliferation, suggesting that tight junctions may regulate CDK4 nuclear localization and cell proliferation through the ZONAB/ZO-1 pathway [32]. These findings confirm that various factors regulate or interact with ZO proteins in the cancer microenvironment. It can be considered that ZO proteins not only act independently but also in conjunction with other factors, thereby significantly influencing the cancer cell environment.

Defense mechanisms in the cancer microenvironment using ZO proteins

As mentioned above, ZO proteins play various roles in the cancer microenvironment and can accelerate cancer progression and development. Therefore, targeting ZO proteins to defend against mechanisms occurring in the cancer microenvironment could potentially suppress the development of cancer cells. ZO proteins contain a PDZ domain that controls intercellular communication and polarization, protein transport, and protein metabolism. This domain is critical for protein complex formation and stability, establishing an important link between extracellular stimuli detected by transmembrane receptors and intracellular responses. It has also been proposed as a potential therapeutic target for various diseases [33]. Previous studies have reported that deletion or modification of the PDZ domain in ZO proteins can affect inflammatory responses and EMT processes [18,34,35]. Specifically targeting the PDZ domain of ZO proteins in cancer therapy could, therefore, provide a means to inhibit cancer progression.

The expression of ZO proteins can also be regulated using natural compounds. Natural products, derived from substances found in nature and synthesized chemically, are often used in basic research and as health supplements. Recent studies have shown that natural compounds affect the cancer microenvironment [36-38]. In addition, among these natural products, curcumin and resveratrol have been reported to influence the expression of ZO proteins. Curcumin, the main active compound in turmeric, has anti-inflammatory properties. In a study investigating the effects of curcumin on intestinal damage and the intestinal mucosal barrier, it was reported that pretreatment with curcumin increased the expression of ZO-1, restoring the epithelial structure and protecting the intestines from damage [39]. Resveratrol, a compound produced by plants in response to stressors like mold or pests, has anticancer, antiviral, and antiaging effects. In a study on the anti-inflammatory properties of resveratrol for the treatment of ulcerative colitis, it was found that resveratrol reduced the expression of ZO-1 and inhibited the Notch receptor 1 (Notch1) pathway in the HT-29 cell (colon adenocarcinoma) model of inflammation induced by lipopolysaccharide. This inhibition led to a reduction in the expression of the inflammatory factors IL-6 and tumor necrosis factor-α, suggesting that resveratrol can regulate the ZO-1 protein by weakening the Notch1 pathway [40]. Therefore, controlling the expression of ZO proteins using natural products could potentially prevent the progression and development of cancer by counteracting mechanisms within the cancer microenvironment.

Ongoing research projects

To date, ZO proteins have been widely studied in various diseases, including cancer. In particular, research related to metastasis and invasion has primarily focused on how ZO proteins link cells and transmit signals between themselves [41,42]. Recently, studies have progressed from cellular-level research to in vivo studies using mice with knocked-out ZO proteins. These studies have confirmed that ZO proteins play critical roles in pathophysiology, structure, and morphology [43,44]. However, the exact mechanisms through which ZO proteins contribute to morphological or physiological functions in vivo remain unclear. Therefore, further research is needed to investigate the mechanisms of action of ZO proteins in vivo and their effects on the cancer microenvironment.

Conclusions

ZO proteins play a crucial role in the cancer microenvironment. These proteins form a structural support around cancer cells, regulating cell adhesion and interacting with various cells to influence cancer development and metastasis. Notably, ZO proteins perform various functions through angiogenesis, inflammatory response, EMT, and interactions with mesenchymal stem cells (Fig. 1). However, since the mechanisms of action may vary depending on the type of cancer and environmental conditions, a defensive strategy tailored to the cancer-specific roles of ZO proteins is necessary. Additionally, the specific mechanisms of ZO protein activity in vivo and their impact on the cancer microenvironment have not been fully elucidated, warranting further research.

Fig. 1.

Schematic representation of the function of ZO proteins in the cancer microenvironment. MSC, mesenchymal stem cell; ZO, zonula occludens; M, macrophage; FOXP3, forkhead box P3; CXCL8, CXC motif chemokine ligand 8; IL-8, interleukin 8; FGF, fibroblast growth factor; EMT, epithelial-mesenchymal transition.

Notes

Conflicts of interest

Hee-Jae Cha is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.

Funding

This work was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korean government (NRF-2021R1A4A1031380).

Author contributions

Conceptualization: HJC. Investigation: MHK. Supervision: HJC. Writing - original draft: MHK. Writing - review & editing: HJC. All authors read and approved the final manuscript.

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