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Xu, Q.;  Du, X.;  Huang, T.;  Zheng, Y.;  Li, Y.;  Huang, D.;  Dai, H.;  Li, E.;  Fang, W. Cell-Cell Junctions in Oesophageal Squamous Cell Carcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/29552 (accessed on 21 December 2025).
Xu Q,  Du X,  Huang T,  Zheng Y,  Li Y,  Huang D, et al. Cell-Cell Junctions in Oesophageal Squamous Cell Carcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/29552. Accessed December 21, 2025.
Xu, Qian-Rui, Xiao-Hui Du, Ting-Ting Huang, Yu-Chun Zheng, Yu-Ling Li, Dan-Yi Huang, Hao-Qiang Dai, En-Min Li, Wang-Kai Fang. "Cell-Cell Junctions in Oesophageal Squamous Cell Carcinoma" Encyclopedia, https://encyclopedia.pub/entry/29552 (accessed December 21, 2025).
Xu, Q.,  Du, X.,  Huang, T.,  Zheng, Y.,  Li, Y.,  Huang, D.,  Dai, H.,  Li, E., & Fang, W. (2022, October 17). Cell-Cell Junctions in Oesophageal Squamous Cell Carcinoma. In Encyclopedia. https://encyclopedia.pub/entry/29552
Xu, Qian-Rui, et al. "Cell-Cell Junctions in Oesophageal Squamous Cell Carcinoma." Encyclopedia. Web. 17 October, 2022.
Cell-Cell Junctions in Oesophageal Squamous Cell Carcinoma
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This entry is adapted from the peer-reviewed paper 10.3390/biom12101378

Cell–cell junctions comprise various structures, including adherens junctions, tight junctions, desmosomes, and gap junctions. They link cells to each other in tissues and regulate tissue homeostasis in critical cellular processes. Recent advances in cell–cell junction research have led to critical discoveries. Cell–cell adhesion components are important for the invasion and metastasis of tumour cells, which are not only related to cell–cell adhesion changes, but they are also involved in critical molecular signal pathways. They are of great significance, especially given that relevant molecular mechanisms are being discovered, there are an increasing number of emerging biomarkers, targeted therapies are becoming a future therapeutic concern, and there is an increased number of therapeutic agents undergoing clinical trials. Oesophageal squamous cell carcinoma (ESCC), the most common histological subtype of oesophageal cancer, is one of the most common cancers to affect epithelial tissue. ESCC progression is accompanied by the abnormal expression or localisation of components at cell–cell junctions.

tight junction oesophageal squamous cell carcinoma gap junction

1. Overview

Epithelial cells exhibit several types of cell–cell junctions that can be classified into adherens junctions, tight junctions, desmosomes, and gap junctions. Cell–cell junctions play an essential role in the maintenance of epithelial homeostasis. During various physiological processes, such as tissue development, wound healing, or tumorigenesis, cellular junctions are reorganised to allow the release or the incorporation of individual cells. Abnormalities in the organisation of these junctions are common in genetic and metabolic disorders of the epithelia [1]. Their compositions are dynamic and regulated by complex protein networks. The imbalance of these networks, caused by oncogenic proteins or pathogens, results in barrier breakdown and eventually leads to cancer; this may be due to the disorder between the partial dismantling and re-establishment of cell–cell contact [2]. Deregulation of molecules in the junctions contributes to tumour metastasis. Loss of cell–cell contact also facilitates the migration of tumour cells to distal sites [3].

2. Tight Junctions

Tight junctions, located at the apical region of cell–cell contacts, have two main functions, serving as both a “fence” and “gate”. As a “fence”, the tight junction restricts the exchange of membrane components between the apical and basolateral cell surface domains. As a “gate”, it regulates paracellular free diffusion of ions and molecules across the epithelial cell sheet, thus acting as an osmotic barrier for the tissues and different compartments of the body [4]. The molecular composition of tight junctions has been widely studied, and it mainly involves the transmembrane claudins, and the adapter protein zonula occludens (ZO), which is connected to claudins in the cytoplasm. In addition, other components, such as tight junction-associated MARVEL proteins (TAMP) (occludin, tricellulin, marvelD3), and junction adhesion molecules (JAMs), are also located around the tight junctions [5].
Claudin is a four transmembrane protein whose positively and negatively charged residues in the first extracellular domain determine the permeability of ions with different sizes and charges. For tight junctions to form in epithelial cells, claudins polymerize linearly to generate tight junction strands in the most apical parts of the lateral membranes [6], and the width of tight junction strands, revealed by freeze-fracture electron microscopy, suggests that two linear claudin polymers associate with each other in an antiparallel double row fashion [7].
Occludin plays a regulatory role in tight junctions and forms a platform for the signal transduction process. It has been determined that a variety of stimuli can regulate the structure and function of tight junctions through occludin, including growth factors (such as hepatocyte growth factor), inflammatory factors (such as interleukin), TNF- α, IFN- γ, and so on; however, tight junctions can form normally without occludin, meaning that the mechanism is undetermined. JAMs are members of an immunoglobulin superfamily that interact with tight junctions and adherens junction proteins to regulate barrier function, cell migration, and cell proliferation [1].
The Zos include ZO-1, ZO-2, and ZO-3. Zos contain a variety of domains, and they interact with various proteins, such as claudins, F-actin, adhesive connection proteins, such as α-Catenin and afadin, and signal proteins [5]. The N-terminus of ZO-1 consists of PSD95, DlgA, and ZO-1 (PDZ) homology domains, an SRC homology 3 (SH3) domain, and a guanylate kinase (GUK) homology domain that interacts with different proteins. The PDZ1 domain interacts with claudins, PDZ3 interacts with JAMs, GUK interacts with occludins, and SH3 interacts with the ZO-1-associated nucleic acid binding protein, (ZONAB)/heat shock 70 kD protein 4 (HSP70RY). ZONAB is a proliferation-regulating transcription factor localised in tight junctions and nuclei. ZONAB enhances proliferation in the nucleus, but ZONAB inhibits proliferation by binding to ZO-1 at the tight junctions [4]. The C-terminus of ZO-1 interacts with F-actin. The function of the interaction between ZO-1and F-actin is not clear; however, it has been predicted that ZO-1 regulates the majority of cytoskeletal tension, and ZO-1 deletion could lead to dysregulated and excessive cytoskeletal tension that would ultimately cause epithelial apical specialisation abnormalities [4][8].

3. Adherens Junctions

The adherens junction regulates the organisation of the cytoplasmic actin cytoskeleton and establishes a hub for cell signalling [9]. It is characterised by two cell membranes, spaced about 10–20 nm apart, and occupied by rod-like molecules bridging the plasma membranes [9][10]. Classical cadherins, such as E-Cadherin, are the primary transmembrane glycoproteins constituting adherens junctions, and they contain five extracellular cadherin repeat domains that engage in Ca2+-dependent trans binding to a cadherin on the opposing cell surface [11]. The cytoplasmic domain of E-Cadherin forms a ternary complex with β-Catenin (a member of the armadillo protein family) and α-Catenin, the former of which is mechanically attached to the actin cytoskeleton [1] after α-Catenin binds to F-actin in a force-dependent manner [12]. p120-Catenin also binds to the ternary complex and regulates the lifetime of E-Cadherin on the plasma membrane [13]. Another immunoglobulin-like adhesion molecule, Nectin, forms calcium-independent intercellular adhesions in adherens junctions [14]. Nectin binds afadin, which also binds α-Catenin [15] and ZO-1 [16] in order to link Catenin-based complexes to the actin cytoskeleton; thus, adherens junctions are closely related to the tight junctions discussed above.

4. Desmosomes

The desmosome is located under the adhesion belt, a speckled anchoring joint among cells. Its principal function is to anchor cytoskeletal keratin intermediate filaments to the cell membrane [17]. Acting as the main intercellular junctions of epithelial cells, desmosomal components can be classified into three types according to gene and function: desmosomal cadherins, armadillo proteins, and plakin proteins [18]. Desmosomal cadherins, which have received the most focus in oesophageal squamous cell carcinoma (ESCC) research [19][20], are transmembrane glycoproteins that rely on calcium for adhesion, and they consist of desmocollins (DSC1-3) and desmogleins (DSG1-4). Their primary function is to mediate the assembly of desmosomes and E-Cadherin maturation [21]. DSC2, the most widely distributed form of DSCs [22][23], plays a role in the interaction between plaque proteins and intermediate filaments to mediate cell–cell adhesion, and it may also be involved in epidermal cell localisation [24]. For other components of the desmosome, the armadillo family includes plakoglobin (PG, also known as γ-Catenin) and plakophilins (Pkps), and the plakin family has desmoplakin (DSP) and envoplakin (EVPL). DSP connects with intermediate filaments.

5. Gap Junctions

The gap junction is an intercellular channel structure encoded by a family of genes called connexins. Unlike other junctions, gap junctions do not prevent substances from passing between cells. Instead, gap junctions allow two adjacent cells to communicate through corresponding channels with connexins (Cxs), and they play an important role in cell communication. The channel comprises two membrane-integrated hemichannels that are supplied by both of the two adjacent cells. Each hemichannel includes a hexameric complex of Cxs proteins [25]. There are at least 21 Cx isoforms in the human genome [26]. Small ions and molecules (1000 Da) directly pass through gap junctions. Gap-junctional intercellular communication (GJIC) is thought to be involved in tissue homeostasis, cell differentiation, and cell growth [27][28].
Reduction or loss of gap junction activity is associated with various human cancers, including ESCC [29][30]; however, the mechanism of action in ESCC remains unknown, and there are only a limited number of studies related to Cx26 and Cx43 [31]. Cx26 and Cx43 are the Cxs constitutively expressed in normal epithelial oesophageal tissue, but in most oesophageal tumours, the expression of Cx26 is absent, and the expression of Cx43 is decreased [32][33]; however, during tumour progression and the acquisition of the malignant phenotype, Cx proteins often translocate from the cell membrane into an intracellular site such as cytoplasm, which causes the number of Cxs to increase in different histological types of malignant tumours [34], and the excessive accumulation of Cxs may be related to cancer progression [35]. A study analysed the expression of Cx43 via immunohistochemical staining and found that Cx43 is expressed at a high frequency in patients with ESCC. Moreover, in patients with high Cx43 expression, the survival rate is lower compared with those that have low Cx43 expression [36]. Another study found no positive staining for the specific expression of Cx26 in normal oesophageal epithelial cells, whereas positive Cx26 expression in tumours was correlated with lymph node metastasis and a low five-year survival rate in ESCC patients. This suggests that the abnormal expression of Cx26 participates in the progression of ESCC [37].
The mechanisms of whether and how Cxs behave in a pro-oncogenic manner are not yet clear; however, it was proposed that the endoplasmic reticulum stress (ER-stress) response may be closely connected with this process. Since endoplasmic reticulum (ER) is a critical organelle with functions that include protein folding and degradation, it is therefore vital to maintain homeostasis in all ER components and machineries [38]. The cancer cells often lead to conditions that promote the build-up of misfolded proteins. The accumulation of unfolded or misfolded proteins leads to stress conditions [39]. Then eukaryotic cells respond rapidly to ER dysfunction through a series of adaptive pathways called ER stress pathways [40], which then activate the unfolded protein response (UPR) in order to maintain ER homeostasis; however, if these processes fail to resolve ER stress, a terminal UPR program takes over and actively signals cell suicide [41]. Although many proteins related to the ER-stress response function in a Golgi-independent manner, the ER-resident ATF6 protein is translocated into the Golgi apparatus, where it is cleaved, and then imported into the nucleus to induce genes that participate in the ER-stress response [34][42]. In experiments on rat skin, translocation of Cx43 might be related to the activation of Wnt signalling, which also plays an important role in β-Catenin phosphorylation, and consequently, E- to N-Cadherin transition [43]. Studies of breast cancer cells found that N-Cadherin/E-Cadherin junctions and Cx43 participate in the composition of the osteogenic niche. This intermediate space allows heterotypic adherens junctions between E-Cadherin on disseminated tumour cells, and N-Cadherin on osteogenic cells, to stimulate mTOR signalling in cancer cells to support growth and metastasis [44][45]; therefore, it is worth exploring their relationship further to help understand the roles in ESCC.
Existing studies point to a model wherein the activity of gap junctions is reduced or lost in most ESCC tumours with a low degree of malignancy. Then, as cancer develops, the abnormal expression and increased intracellular Cx expression will occur in poorly differentiated ESCC cells, which is indicative of poor patient prognosis.

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Qian-Rui Xu ,
Xiao-Hui Du
,
Ting-Ting Huang
,
Yu-Chun Zheng
,
Yu-Ling Li
, Dan-Yi Huang ,
Hao-Qiang Dai
, En-Min Li , Wang-Kai Fang
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Update Date: 18 Oct 2022
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