Junctional adhesion molecule-A (JAM-A) in gynecological cancers: Current state of knowledge

Introduction

Multiprotein complexes found in vertebrate intercellular junctions (i.e., tight junctions, gap junctions, desmosomes, and adherens junctions) facilitate the transmission of information between neighboring cells and cell-cell adhesion (Zihni et al., 2016; Rusu and Georgiou, 2020). Tight junctions (TJs) are structures located directly below the apical surface in the lateral epithelial and endothelial cell membrane (Rusu and Georgiou, 2020). Mainly, TJs are involved in the regulation of cellular processes such as maintaining the apical-basal polarization of cells (intramembrane diffusion barrier) and sealing the space between adjacent cells (paracellular diffusion barrier) (Zihni et al., 2016). TJs also play the role of signaling platform which regulates gene expression (Gonzalez-Mariscal et al., 2014), proliferation (Diaz-Coranguez et al., 2019), and differentiation of cells (Zihni et al., 2014).

Junctional adhesion molecule-A (JAM-A), also known as the F11 receptor (F11R), is one of the TJ components (Kornecki et al., 1990; Martìn-Padura et al., 1998) and is also expressed on circulating platelets and leukocytes (Wang and Chen, 2022). Shortly, JAM-A is a transmembrane glycoprotein that contains an extracellular region at the N-terminus with two immunoglobulin (Ig)-like domains, a transmembrane segment, and a short cytosolic tail at the C-terminus (Martìn-Padura et al., 1998; Prota et al., 2003; Steinbacher et al., 2018).

Moreover, it regulates many cellular processes, including angiogenesis (Naik et al., 2008), cell migration (Azari et al., 2010; Wang and Liu, 2022) and adhesion (Mandell et al., 2005), leukocyte transendothelial migration (Corada et al., 2005; Khandoga et al., 2005), intercellular permeability (Laukoetter et al., 2007), epithelial-to-mesenchymal transition (EMT) (Communal et al., 2020) and platelet activation (Babinska et al., 2002). In the literature, JAM-A is described as a protein involved in the pathogenesis of neurological disorders (Padden et al., 2007), cardiovascular diseases (Babinska et al., 2019; Koenen and Weber, 2022; Rath et al., 2022; Wang and Chen, 2022), rheumatoid arthritis (Fang et al., 2016), inflammatory bowel disease (Vetrano and Danese, 2009), and many types of neoplastic diseases including breast (McSherry et al., 2009; Murakami et al., 2011; Vellanki et al., 2019; Bednarek et al., 2020; Vences-Catalan et al., 2021; Smith et al., 2022), lung (Magara et al., 2017; Zhao et al., 2017), nasopharyngeal (Jiang et al., 2019; Dai et al., 2021), head and neck (Kurose et al., 2016; Kakiuchi et al., 2021), testicular (Tarulli et al., 2013), thyroid (Orlandella et al., 2019), colorectal (Caykara et al., 2019; Lampis et al., 2021), gastric (Huang et al., 2014), endometrial (Koshiba et al., 2009), cervical (Akimoto et al., 2016; Murakami et al., 2021), and ovarian cancer (Boljevic et al., 2019; Communal et al., 2020). The involvement of JAM-A in various malignancies progression and its correlation with poor patient prognosis are reviewed in detail in our previous article (Czubak-Prowizor et al., 2022).

For a long time, the loss of TJ-related proteins was considered necessary in the early stages of cancer metastasis (Lee et al., 2005; Martin and Jiang, 2009; Martin et al., 2010; Suren et al., 2014; Shimada et al., 2017). The overexpression of proteins located in TJs may also activate intracellular signaling pathways responsible for metastasis and tumorigenesis (Leech et al., 2015). Depending on the cancer type, both low and high JAM-A levels correlate with poor clinical prognosis in cancer patients (Czubak-Prowizor et al., 2022). A positive correlation (i.e., JAM-A overexpression was associated with adverse clinical outcomes) was observed in breast cancer (McSherry et al., 2009; Murakami et al., 2011; Leech et al., 2018; Cruz et al., 2021), lung cancer (Magara et al., 2017; Zhao et al., 2017), glioblastoma (Rosager et al., 2017), ovarian cancer (Boljevic et al., 2019; Communal et al., 2020), multiple myeloma (Solimando et al., 2018; Solimando et al., 2020), lymphoma (Xu et al., 2017), oral squamous cell carcinoma (Upadhaya et al., 2019), and cervical adenocarcinoma (Akimoto et al., 2016; Murakami et al., 2021). While a negative correlation (i.e., underexpression of JAM-A was associated with adverse clinical outcomes) was described in colorectal cancer (Lampis et al., 2021), endometrial carcinoma (Koshiba et al., 2009), pancreatic cancer (Fong et al., 2012), and gastric cancer (Huang et al., 2014). The tissue-specific role of JAM-A in the progression and invasiveness of neoplastic diseases is complex and not fully understood; therefore, this protein is still the subject of discussion and research interest.

The following viewpoint article focuses on the current knowledge about JAM-A participation in gynecological malignancies progression and metastasis.

Recent Developments

Most gynecological cancer-related deaths in women are caused by epithelial ovarian cancer (EOC) development. The most common and aggressive histological type of EOC is high-grade serous carcinoma of uterine adnexa (HGSC). The main factors contributing to the high mortality rate in EOC patients are the lack of specific symptoms at the initial stages of the disease, which temporizes the diagnosis, the lack of effective screening tests, and the development of chemoresistance. Finding new biomarkers of ovarian cancer is so crucial. Inconsistent data about JAM-A expression in EOC is presented in the literature (Boljevic et al., 2019; Communal et al., 2020). Among other gynecological malignancies, disturbances in JAM-A levels have also been studied in the cervical (Akimoto et al., 2016; Murakami et al., 2021) and endometrial carcinoma (Koshiba et al., 2009).

Epithelial ovarian cancer

In 2019, Boljevic et al. (2019) first published results showing the clinical significance of JAM-A gene expression in the pathogenesis of EOC. JAM-A gene expression levels were determined in 44 epithelial ovarian cancer formalin-fixed paraffin-embedded (FFPE) tissue blocks using reverse transcription and quantitative real-time polymerase chain reaction (RT-qPCR) method. In the tested EOC samples, 75% were represented by serous histological type, and approximately 61.5% were advanced International Federation of Gynecologists and Obstetricians (FIGO) stage (III + IV). Authors reported a worse overall survival rate in EOC patients characterized by JAM-A overexpression compared to patients with low JAM-A gene expression. Furthermore, high JAM-A gene expression was related to the advanced FIGO staging system suggesting JAM-A participation in EOC progression. Based on their studies, they proposed the JAM-A gene as a potential prognostic and diagnostic biomarker in EOC (Boljevic et al., 2019).

Unfortunately, these studies did not identify the molecular mechanisms by which JAM-A contributes to the EOC progression, which would confirm and strengthen the obtained results. Additionally, this is a rather retrospective study because researchers used only one laboratory method and then statistically analyzed using receiver operating characteristic (ROC) curve analysis, Fisher’s exact test, Kaplan-Meier method, and univariate Cox regression analysis (Boljevic et al., 2019).

High-grade serous carcinoma of uterine adnexa

High-grade serous carcinoma of uterine adnexa (HGSC) is one of the EOC histotypes. In 2020, Communal et al. (2020) indicated that shorter overall survival and shorter progression-free survival (i.e., poor clinical outcome parameters) were associated with low JAM-A protein expression (revealed using the Kaplan–Meier method and univariate Cox regression analysis). This data was inconsistent with results presented by Boljevic et al. (2019) one year earlier. In this study, JAM-A protein levels were determined using immunofluorescent staining with digital image analysis in HGSC FFPE tissue microarrays (1,526 clinical samples). Based on clinicopathologic characteristics, most of the tested samples were from patients in the III FIGO stage, high-grade serous subtype, and without chemotherapy before the surgery in which the material for the study was collected. Normal fallopian tube tissues (15 samples) from women without gynecological cancer were also included in the study as a control (Communal et al., 2020).

JAM-A expression analysis revealed prominent variability in its expression in HGSC clinical samples. Importantly, statistically significant differences in JAM-A expression between normal vs. cancer tissues were not observed. However, decreased JAM-A expression characterized samples from patients in the III + IV FIGO stage in comparison to the I + II FIGO stage. HGSC tissues indicated cell apico-basal polarity loss (Communal et al., 2020).

Moreover, analysis of proteomic data from the Clinical Proteomic Tumor Analysis Consortium revealed increased EMT in tumor samples characterized by low JAM-A protein levels. It suggested that the EMT-dependent mechanism could be responsible for the observed results (Communal et al., 2020).

The authors also identified the JAM-A protein as a candidate for the novel molecular biomarker of HGSC, based on its high expression on the cell surface (analysis of 26 human HGSC-derived cell lines using the flow cytometric method). Subsequently, protein expression levels were determined in 101 primary HGSC tissues and 15 normal fallopian tube tissues as control using immunofluorescence staining. It was exhibited that in the tested tissue cohort, JAM-A could be a prognostic predictor of poor outcomes (Communal et al., 2020).

Cervical adenocarcinoma

Tumor surgical specimens from patients with cervical adenocarcinoma and adenocarcinoma in situ characterized the higher expression of some TJs proteins, exactly JAM-A, claudin-1, claudin-4, and claudin-7 in comparison to non-neoplastic tissues (Akimoto et al., 2016). In this study, 55 cancer patients were included. Selected proteins in tested specimens were stained immunohistochemically. In cervical adenocarcinoma cells, JAM-A and claudin-1 were delocalized from the apical-most part of the intercellular membrane and spread to the whole membrane.

Based on these findings, the authors proposed JAM-A and claudin-1 as potential diagnostic markers of cervical adenocarcinoma, which distinguish cancer cells from the adjacent cervical columnar epithelium (normal cells) with high specificity and sensitivity (ROC curve analysis) (Akimoto et al., 2016).

In a recent study, the same research group from Sapporo (Japan) showed that aberrant JAM-A expression significantly influenced uterine cervical adenocarcinoma progression (i.e., higher malignant potential) through JAM-A interaction with CD155 (also called the poliovirus receptor) (Murakami et al., 2021). Also suggested that cell surface JAM-A and CD155 could be potential therapeutic targets. The authors tested 67 surgical specimens by immunohistochemical staining and in human HCA1 cervical adenocarcinoma cell line after stable JAM-A knockout (KO) determining cell proliferation, colony formation, and collective migration. JAM-A overexpression in tissues from cancer patients correlated with shorter relapse-free survival, and overall survival (poor clinical outcome and prognosis). In the HCA1 cell line, after JAM-A KO was observed, there was a decrease in cell migration ability, cell proliferation, and colony formation. Of note, tested specific antibodies against JAM-A suppressed cell proliferation and indicated that JAM-A loss contributes to intensified sensitivity of the drug against this cancer type (Murakami et al., 2021).

Endometrial carcinoma

Human endometrial malignancy was the last tested gynecological cancer type in the context of the role of JAM-A in its pathogenesis (Koshiba et al., 2009). Poor clinical outcomes, described as short patient progression-free survival and overall survival (Kaplan–Meier curves), were correlated with low JAM-A levels. Additionally, histologic grade, stage, and myometrial invasion are negatively associated with JAM-A expression. JAM-A could be a prognostic marker of this cancer type because its level is decreased in advanced and high-grade histotypes (Koshiba et al., 2009).

In 3D-cultured human endometrial cancer cells studies, particularly in the KLE cell line, a poorly differentiated adenocarcinoma cell line, JAM-A expression was lower than in the Ishikawa cell line, which is a well-differentiated cancer cell line. Furthermore, the JAM-A mRNA level in the 3D-culture of Ishikawa cells was significantly higher than in these cells cultured in a monolayer (Koshiba et al., 2009). The obtained results show a significant difference between the applied research methods, simultaneously indicating the validity of using 3D culture.

In the described study, JAM-A expression in human tissues was determined immunohistochemically, but in adenocarcinoma cell lines, also by RT-qPCR. The study included 24 normal endometrial tissue samples and endometrial carcinoma tissue specimens from 50 women (Koshiba et al., 2009).

Conclusion

Over the past decades, aberrant JAM-A expression and its function in the pathogenesis of neoplastic diseases, including gynecological cancers, have been the subjects of research interest. To the best of our knowledge, contradictory JAM-A roles in various cancer-type progression suggest that its influence is complex and tumor-type specific. Nowadays, only a few studies are available about the JAM-A role in gynecological cancers (Fig. 1) (Koshiba et al., 2009; Akimoto et al., 2016; Boljevic et al., 2019; Communal et al., 2020; Murakami et al., 2021). To sum up, possible mechanisms by which aberrant JAM-A levels could influence gynecological cancer development and progression are the cell apico-basal polarity loss, JAM-A delocalization from the most apical part of the intracellular membrane to the whole membrane, and increased EMT which takes part in the tumor development and progression. Disturbances of the described processes or their intensification could significantly affect the gynecological cancer progression.

Figure 1: Aberrant expression of JAM-A gene/protein in gynecological cancers and its association with poor clinical parameters. This figure is designed using resources from Freepik.com.

Conflicting data about JAM-A expression level in EOC has been described in the literature (Boljevic et al., 2019; Communal et al., 2020). These studies had some limitations. Boljevic et al. (2019) determined the JAM-A gene expression levels using the RT-qPCR method in only 44 EOC tissue blocks. The tested EOC cohort was not homogeneous (only 26 samples could be HGSC). To strengthen the obtained results, the authors should also check the JAM-A protein level, add a control group to the research, choose a more homogeneous study cohort, and try to identify the possible molecular mechanisms by which JAM-A contributes to the EOC progression. In our opinion, this research is rather a retrospective study because researchers used only one laboratory method on a small EOC cohort and then performed a statistical analysis. One year later, Communal et al. (2020) published their studies determining JAM-A protein levels using immunofluorescent staining of 1,526 clinical samples from patients with HGSC (the most lethal EOC histotype). The authors also included normal fallopian tube tissues as a control cohort. Importantly, statistically significant differences in JAM-A protein expression between normal vs. cancer tissues were not observed—probably because of a significant difference between the size of the study groups (control: 15 samples, cancer: 1,526 samples). Moreover, the authors suggest that the EMT-dependent mechanism could be responsible for the obtained results. These discrepancies may be related to the large differences in the study group, as well as their heterogeneity and the use of only one experimental method.

In conclusion, the role of JAM-A in the tumor progression and metastasis of gynecological cancers is poorly understood and requires further research. Also, the underlying molecular mechanisms and pathways responsible for multiple JAM-A functions were not fully elucidated and need to be identified. Finding appropriate novel molecular cancer biomarkers may reduce observed very high mortality rates and could contribute to personalized treatment development.

Funding Statement: The authors received no specific funding for this study.

Author Contributions: The authors confirm their contribution to the paper as follows: conception and design: KCP, MS; data collection: KCP; draft manuscript preparation: KCP; manuscript revision: MS, KCP. All authors contributed to the writing and approved the final version of the manuscript.

Availability of Data and Materials: Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Ethics Approval: Not applicable.

Conflicts of Interest: The authors declare that they have no conflicts of interest to report regarding the present study.

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