The monolayer epithelium is the largest tissue lining in a number of human organs, and its integrity is maintained by the cell junction complex. Tight junctions (TJs) exist in the junctional complexes of epithelial and endothelial cells, and serve crucial roles in cell polarity, adhesion and permeability (1). TJs also maintain the integrity of the tissue structure and participate in transmembrane movement and signal transduction inside and outside of cells (2). A decrease in TJ integrity and an increase in cell bypass permeability are characteristics of tumours and inflamed tissues (3). TJs also have adhesive properties and can prevent the shedding of epithelial cells. The initial stage of tumour metastasis is a disconnect between tumour and endothelial cells. Therefore, TJs are the first obstacle that must be overcome in tumour metastasis (4). The decrease in TJ integrity leads to the perfusion and extravasation of cancer cells through the endothelial barrier (5). TJs are composed of three basic membrane proteins: Occludin, claudin (CLDN) and junction adhesion molecules. The CLDN protein family serves a key role in the functions of TJs (6) (Fig. 1), including helping regulate defence and barrier functions, and differentiation and polarity in epithelial and endothelial cells (7). Tumour progression is characterized by the migration, invasion and metastasis of cancer cells. CLDNs are believed to serve a significant role in these processes as their loss contributes to the loss of cell junctions in a tissue-dependent manner. CLDN expression can affect cancer progression in several ways: First, changes in CLDN expression cause TJ disorder and leakage, which is conducive to tumour metastasis and invasion; second, a decrease in cell polarity increases the supply of nutrition and growth factors to the tumour, and increases tumour cell expansion; and third, a decrease in intercellular adhesion may increase the risk of metastasis and promote tumour invasion (8). The CLDN family forms homologous and heterologous interactions between adjacent cells and is a key regulator of tumorigenesis and metastasis. Classic CLDNs (CLDNs 1–10, 14, 15, 17, and 19) also exhibit a much stronger sequence homology than the non-classic CLDNs (CLDNs 11–13, 16, 18, and 20–27) (9) (Fig. 2). Recent findings have shown that abnormal expression of CLDNs is closely related to the occurrence, progression and prognosis of tumours (10). Specifically, the CLDN family member CLDN6 is expressed in numerous tumours but rarely found in adult normal tissues (11). Although some studies have reported results that contradict this, the high expression of CLDN6 in certain tumours makes CLDN6 a potential therapeutic target in these tumour types. Therefore, the present study reviewed the literature on CLDN6, including information on its structure, expression in different tumours, regulatory mechanisms and therapeutic prospects.

CLDN6 is one of 27 members of the CLDN family; it is located on chromosome 16p13.3 and has a molecular weight of 23 kDa (12). CLDN6 has four transmembrane domains and a PDZ-binding region at the carboxyl end of the cytoplasm. This CLDN can bind with signal proteins and cytoskeletal proteins, and participate in the cellular response to external and intracellular signal transmission (13). CLDN6 is the only CLDN to potentially show specificity, as it can activate cell adhesion signals and regulate the activity of nuclear receptors (14). CLDN6 is expressed in a variety of embryonic epithelia, induces epithelial cell junction formation and polarity, and participates in the differentiation of stem cells into epithelial cells. Overall, CLDN6 is an important component of the CLDN family and serves a substantial role in maintaining the function of TJs (15).

Previous findings have shown that changes in CLDN expression cause TJ disorders and leakage (16,17). This decrease in cell polarity increases the supply of nutrition and growth factors for tumour cells. In addition, the decrease in intercellular adhesion may increase the metastatic potential (18). Previous findings have shown that as a member of the CLDN family, CLDN6 is strongly expressed in the foetal stomach, lung and kidney, but not in healthy adult tissues (19,20). However, other studies have not reached the same conclusion (21,22), and the specific expression and regulatory mechanisms for CLDN6 remain unclear or controversial. Regardless, it is accepted that CLDN6 is expressed in a variety of tumours and serves an important role in the occurrence and development of tumours. The known expression and regulatory mechanisms of CLDN6 in various tumour types are shown in Table I.

Previous findings have shown that cancer stem cells (CSCs) are responsible for cancer treatment failure and drug resistance, and that CSCs serve an important role in tumour recurrence, metastasis and drug resistance. Therefore, understanding the factors that regulate CSCs has become very important (60,61). In mouse stem cells, CLDN6 may trigger epithelial morphogenesis, while the expression of CLDN6 constitutes an early marker of embryonic stem cells (62,63). Therefore, it is possible that CLDN6 may affect the biological functions of CSCs.

Chemotherapy is one of the primary treatments for breast cancer, and chemotherapy resistance is the main obstacle in breast cancer treatment (64). In a previous study (65), the expression of CLDN6 was significantly higher in the MCF-7/MDR cell line than in the MCF-7 cell line. The high expression of CLDN6 in MCF-7/MDR cells increased the resistance to Adriamycin (ADM), 5-fluorouracil and cisplatin, while the silencing of CLDN6 enhanced the killing effect of those drugs on the MCF-7/MDR cell line. It is also possible that CLDN6 is involved in the regulation of drug resistance in human breast cancer cells. The mechanism may be through CLDN6 regulating glutathione S-transferase π1 (GSTP1) to promote the chemotherapeutic resistance of MCF-7 cells through p53, as GSTP1 expression and enzyme activity is regulated by p53. In cells that overexpress MCF-7, the expression of GSTP1 was upregulated (65). Furthermore, CLDN6 interacts with p53 to inhibit the transfer of p53 from the cell nucleus to the cytoplasm, leading to drug resistance. CLDN6 can also enhance the drug resistance of breast cancer cells to ADM by activating the AF-6/ERK signalling pathway and upregulating the characteristics of breast cancer cells (66). These findings may provide a new target and strategy for cancer treatment.

In the study by Reinhard et al (11), CLDN6 was specifically expressed in a variety of tumours but not in healthy tissues. Although a number of research conclusions contradict this (39,50,51), CLDN6 still has the potential to act as a tumour gene target in cancer types, such as liver, ovarian and endometrial cancer, and to provide new strategies for tumour treatment. The treatment modalities for this include antibody drug-binding targets, radionuclide therapeutic targets and new antibody therapeutic targets, among others.

A new patent for a monoclonal antibody against CLDN6 has been shown to be effective against testicular germ cell tumours (TGCTs). The use of CLDN6 antibody can block tumour growth and prolong the life of patients with TGCT. The presence of tumour-associated antigens can induce strong and persistent antigen-specific T-cell responses, break the immune system tolerance to endogenous self-antigens and produce effective antitumour effects (67).

Antibody drug conjugates (ADCs) are monoclonal antibodies that bind to cytotoxic drugs (68). The antibodies used by ADCs have high specificity for tumour cell surface proteins and can specifically kill tumour cells. ADCs can transport drugs to tumour sites through targeted drug delivery and decrease the toxicity of cytotoxic drugs to normal tissues (69,70). As CLDN6 is a specific antigen found in some tumours, it may be a potential target for ADC drugs.

Targeted radionuclide therapy (TRT) uses a molecular carrier with a high affinity for tumour cell surface antigens to transport nuclides to tumour cells and sites of metastasis for treatment. Drugs containing radionuclides are targeted to accumulate in tumour tissues, which directly affects cancer cells and avoids damaging normal cells (71). TRT combines the specificity of molecular targeting and the cytotoxicity of ionising radiation to reduce toxicity to healthy tissues and provides a more effective tumour treatment method (72). This may be an important direction for tumour treatment in the future. As a specific antigen in some tumours, CLDN6 may be an effective tumour-targeting vector.

Recent findings have shown that chimeric antigen receptor (CAR)-T cells can be used to treat tumours expressing chimeric antigen receptors after the gene transformation of B-cell malignant tumours (11). However, due to the limitations of tumour-specific targets, CAR-T cell therapy is ineffective in patients with solid tumours (11). CLDN6 is a surface antigen of carcinoembryonic cells and has an ideal expression profile for CAR-T cells. Although some research conclusions are inconsistent on this topic, study results show that CLDN6 LPX can cause CLDN6-CAR-T proliferation and survival effectively in vivo, allowing CAR-T cells to treat solid tumours (73). This provides a new strategy for the treatment of solid tumours using CAR-T cells.

In addition, it has been found that CLDN6-mediated measles virus (MV) can induce tumour-associated antigen-specific humoral immunity. Mice inoculated with the CLDN6 vaccine showed targeted complement-dependent cytotoxicity with cytolytic activity. MV combined with a tumour lytic effect and the CLDN6 tumour vaccine was able to break the tolerance to endogenous tumour antigens and produce a highly effective and specific antitumour immune response (74). These studies suggest that CLDN6 may provide a new strategy for tumour vaccine treatments of solid tumours.

Reinhard et al (11) believed that CLDN6 is a strictly carcinoembryonic antigen that is expressed exclusively in tumour tissues. However, the present study reviewed the expression of CLDN6 in various tumours and found that the research conclusions for several tumour types were not completely consistent or were contradictory. Possible reasons for inconsistent conclusions include heterogeneity in tumours, use of monoclonal antibodies, different experimental methods and the interpretation of the results. In addition, the role of CLDN6 differs by tumour type, as it promotes some tumours, inhibits others and shows inconsistent (promotional and inhibitory) effects in some tumours.

However, in liver, ovarian, endometrial and oesophageal cancer types, the expression of CLDN6 is consistently expressed in tumour tissues, compared with no or less expression in the surrounding normal tissues. Therefore, CLDN6 has potential as a carcinoembryonic antigen and a therapeutic target for these tumours.

The reason for CLDN6 expression being upregulated in some tumours and downregulated in others remains unclear. Possible reasons include detection errors or CLDN6 having different roles in different tumours. This area requires further research. Moreover, currently, there are no studies of whether a relationship exists between these tumours; this needs to be further explored. The expression of other CLDNs and their synergistic effects with CLDN6 have been reported. In breast cancer, overexpression of CLDN3, −4 and −7 was primarily dependent on oestrogen receptor-status, whereas overexpression of CLDN6 and high membranous expression of CLDN1 were independent of other characteristics (24). Another study showed that CLDN5, CLDN9, CLDN12 and CLDN13 were not expressed in breast carcinoma tissues or non-neoplastic tissues (22). In addition, CLDN1, CLDN3, CLDN8 and CLDN10 were expressed in breast carcinoma and non-neoplastic tissues, but there was no significant difference between the expression of all these CLDN proteins. The expression of CLDN2, CLDN6 and CLDN14 was downregulated, while the expression of CLDN11 was upregulated in breast carcinoma compared with those in non-neoplastic tissues. In addition, a distinct prognostic significance in the expression of CLDN3 and mostly of CLDN4 between triple-negative and luminal breast carcinomas was identified (75). In gastric cancer, the expression of CLDN2 and CLDN6 was downregulated in gastric cancer tissue, while the expression of CLDN11 was upregulated (36). CLDN6 induces MMP2 activation through CLDN1 membrane expression, which in turn promotes cell migration and invasiveness (44). CLDN6 expression was high in both intestinal- and diffuse-type gastric adenocarcinomas. CLDN7 was expressed mainly in the diffuse-type, whereas CLDN9 was primarily found in the apical membrane of the gland cells in the intestinal-type (40). In addition, CLDN7, −3 and −4 have been detected in gastric cancer (76–78).

CLDN6 has more than one regulatory mechanism in a variety of tumours, such as breast and gastric cancer. These mechanisms may work synergistically. However, the primary mechanism, as well as the effect(s) of different regulatory mechanisms, remain to be determined and require further study.

Although there are still a number of controversies regarding the expression and regulation mechanisms of CLDN6, CLDN6 is a potential antigen and has the potential to be used as a target for a variety of tumours and treatments.

CLDN6 is expressed in a variety of tumours, and its expression levels differ by tumour type. In some tumours, research consistently shows that CLDN6 is expressed in tumour tissues, but is not expressed or expressed at low levels in surrounding tissues. These include liver, ovarian, endometrial and oesophageal cancer, and AT/RTs, among others. In these tumours, CLDN6 has potential as a carcinoembryonic antigen and a therapeutic target. However, in other tumours, the expression levels of CLDN6 between tumour and surrounding tissues differ from one another or are even the opposite. These include breast, gastric, cervical and lung cancer. In the future, CLDN6 may be used as a target for a variety of therapeutic types such as antibody-drug radionuclide-targeted drugs and ADCs.