The increasing incidence and mortality rates of endometrial cancer highlight the critical need for new molecular biomarkers(30–32). These biomarkers are essential for early diagnosis, accurate prognosis, and the development of effective treatment strategies. Advances in molecular classification, particularly in identifying distinct subtypes, are revolutionizing the approach to endometrial cancer care. This progress, combined with emerging blood-based biomarkers, significantly enhances early detection, enables more precise prognostic assessments, and supports the implementation of targeted therapies(33–36). Broadening the search for and application of these molecular markers is pivotal in advancing personalized medicine, leading to more customized and efficacious treatments, ultimately improving outcomes and the quality of life for patients with endometrial cancer.
Recent analyses have confirmed CPA4 as a potential biomarker for early cancer diagnosis. In bladder cancer, CPA4 overexpression correlates with poor survival outcomes, similar to findings in endometrial cancer. The link between CPA4 expression and immune cell infiltration in tumors, as evidenced in bladder cancer, may also extend to endometrial cancer, considering the immune system's role in cancer development and progression(18).
The Human Protein Atlas notes CPA4 as a cancer-enhanced gene in certain cancers, such as cervical and head and neck cancers. This suggests a broader oncogenic role for CPA4 across various malignancies, possibly including endometrial cancer. The expression of CPA4 in the endometrium has been documented, with specific data on its RNA expression levels and cell-type specificity, which may inform its expression patterns in endometrial cancer.
Studies in other cancer types, such as breast cancer, have found serum and mRNA levels of CPA4 to be associated with disease aggressiveness and progression, highlighting its potential as a diagnostic and prognostic marker(19). The observed correlation between CPA4 expression and Ki67, a marker of proliferation, could suggest a role in tumor growth and histological grading, which may be explored further in endometrial cancer.
Given the complexity of cancer biology, these findings should be contextualized within the larger framework of tumor microenvironment interactions and genetic variability among patients. The integration of CPA4 expression data with clinical outcomes and molecular profiling in endometrial cancer could provide insights into its potential as a therapeutic target or a component of prognostic models.
To strengthen the discussion, further research could focus on the functional role of CPA4 in endometrial cancer, exploring how its expression affects tumor behavior and response to therapy, and how it might interact with known pathways of endometrial carcinogenesis.
To elucidate the role of CPA4 in tumorigenesis and its association with the 16 hub genes identified in single-gene differential analysis and correlation analysis, an integrative approach is warranted. These hub genes include S100A7, IVL, members of the SPRR family, CASP14, RPTN, CDSN, PI3, and LOR. The comprehensive analysis of literature indicates a multifaceted role of CPA4 in cancer, particularly through its association with hub genes involved in keratinocyte differentiation and function. The exploration of these hub genes and their relationship to cancer can provide insights into the potential functions of CPA4 in endometrial cancer.
S100A7, also known as psoriasin, is associated with tumor progression and has been suggested as a potential diagnostic and prognostic biomarker for esophageal cancer(37, 38). Its role in promoting migration, invasion, and metastasis of human cancer cells highlights its involvement in aggressive cancer behavior(38). Moreover, it has been implicated in breast cancer progression, indicating its relevance across different types of cancers(39, 40).
The IVL gene, which codes for involucrin, a protein involved in the formation of the cell envelope in keratinocytes, shows a pattern of downregulation in oral malignancies and is associated with poor differentiation and reduced overall survival(41). This loss of expression might be indicative of a compromised epithelial barrier, which could be relevant to the progression of endometrial cancer.
The SPRR family genes are associated with increased epithelial proliferation and malignant processes(42). Specifically, SPRR1B has been identified as a significant prognostic gene in lung adenocarcinoma, indicating its role in cancer prognosis(43). The involvement of these genes in colorectal tumors and their upregulation in lung squamous carcinoma further underscore their importance in tumorigenesis(44, 45).
CASP14, a member of the caspase family, is notably higher in triple-negative breast cancer (TNBC) tissues compared to other subtypes, linking it to cancer aggressiveness(46). It has been implicated in brain metastatic breast cancer and is associated with cancer progression in ovarian and colon cancer(47, 48).
The collective findings from these genes suggest that CPA4, through its interaction with them, may be involved in cell differentiation, immune regulation, and the epithelial-to-mesenchymal transition, all of which are pivotal in cancer progression. Therefore, by understanding the functions of these hub genes, we can predict the potential role of CPA4 in endometrial cancer, particularly in its capacity to affect cell proliferation, differentiation, and possibly immune evasion.
The above synthesis indicates that CPA4, in conjunction with its associated hub genes, may be a key player in the complex molecular pathways that contribute to the development and progression of endometrial cancer. It could potentially serve as a biomarker for cancer aggressiveness and a target for therapeutic intervention. Future research should focus on elucidating the precise molecular mechanisms by which CPA4 and these hub genes contribute to endometrial carcinogenesis and on verifying these findings in clinical settings.
The functional enrichment analyses of CPA4 and its differentially expressed genes in the context of endometrial cancer progression have brought to light the significance of several biological processes and molecular functions. The keratinization process, which involves the production of the protective protein keratin, though generally a protective mechanism for the skin, can abnormally contribute to the development of cancers like squamous cell carcinoma. This aberrant keratinization indicates a potential role for CPA4 in epithelial tumorigenesis, given keratins' active involvement in cancer cell invasion, metastasis, and treatment responsiveness(49).
Further examination reveals that CPA4-associated genes are actively involved in G-protein coupled receptor (GPCR) binding, an integral part of cellular signaling that governs tumorigenesis including proliferation, invasion, and survival(50–52). The dysregulation of GPCRs is a common feature in various cancers, implicating CPA4 in the modulation of these receptors, possibly influencing cancer stem cell maintenance and progression(53).
The estrogen signaling pathway's enrichment suggests that CPA4 may also play a role in hormone-dependent cellular processes. Estrogens are known to modify the DNA damage response and DNA repair mechanisms, leading to cancer progression and chemoresistance(54–56). Given the prominence of estrogen signaling in endometrial cancer, CPA4 could influence disease progression by interacting with this pathway(57).
Complement and coagulation cascades, part of the innate immune response, are also implicated in cancer progression, with these pathways potentially correlating with chemosensitivity and patient survival(58). The involvement of CPA4 in these cascades indicates a potential impact on the inflammatory response and tumor microenvironment, which are crucial for cancer development and metastasis(59, 60).
Moreover, the KRAS signaling pathway, which is central to cell growth, differentiation, and survival, is often dysregulated in cancer due to mutations(61, 62). CPA4's association with this pathway suggests it may influence the tumorigenesis process, particularly since KRAS mutations lead to uncontrolled cell proliferation and are present in a significant fraction of cancers(63, 64).
Lastly, the epithelial-to-mesenchymal transition (EMT) process, which is facilitated by CPA4-related pathways, is critical in cancer progression as it enables tumor cells to disseminate, invade, and form metastases(65, 66). The association with EMT also highlights CPA4's possible contribution to the aggressive behavior of endometrial cancer cells, including their chemoresistance and poor prognosis.
In summary, CPA4 is poised at the intersection of multiple signaling pathways that are critical for the progression of endometrial cancer. These include the regulation of epithelial cell function, immune system interactions, hormonal responses, and the cell's invasive and metastatic capabilities. As a result, CPA4 emerges as a potential biomarker for cancer aggressiveness and a promising target for therapeutic intervention. Future research should focus on elucidating CPA4's molecular mechanisms within these pathways to provide new insights into endometrial cancer's molecular underpinnings and pave the way for novel therapeutic strategies.
Utilizing multivariate Cox regression results, a predictive tool in the form of a nomogram plot was constructed to analyze the model's accuracy. The survival prediction plots for 1, 3, and 5 years showed a good correlation with actual values, suggesting that this model may emerge as a novel and valuable method for prognosis estimation. Previous extensive research on molecular biomarkers for endometrial cancer has proposed the use of both protein-coding RNAs and non-coding RNAs as predictors for the incidence and prognosis of the disease(67, 68). Studies have indicated that genes such as PTEN, KNL1, PPP2R1A, PPP1R14B, L1CAM, and CTNNB1 are associated with the occurrence, progression, and prognosis of UCEC(69). These findings support the feasibility of CPA4 as a potential molecular marker to aid in the diagnosis and prognostic assessment of endometrial cancer.
In the last, the downregulation of CPA4 via shRNA in HEC-1-A and Ishikawa cell lines led to decreased cell viability, migration, invasion capabilities, an increase in apoptotic cells, and a cell cycle arrest predominantly in the G2/M phase. These cellular experiment outcomes further corroborate the close relationship between CPA4 and cancer cell proliferation, invasion, and metastasis, positioning CPA4 as a potential molecular target for cancer therapy.
In light of recent literature, such as the comprehensive analysis of CPA4 as a poor prognostic biomarker correlated with immune cell infiltration in bladder cancer(18), it is evident that CPA4's overexpression is associated with shorter overall survival and may influence immune response via markers related to T cell exhaustion. These findings enhance the proposition of CPA4 as a valuable biomarker for the diagnosis and prognosis of endometrial cancer, supporting its potential as a target for therapeutic interventions. The investigation into CPA4's role in endometrial cancer progression is a significant step towards understanding the molecular underpinnings of this malignancy and devising new strategies for its management.
In summary, the elevated expression of CPA4 has been linked to the progression, metastasis, and invasion of endometrial cancer, as well as the suppression of immune responses, suggesting that CPA4 could serve as a potential diagnostic and therapeutic biomarker and an independent risk factor for prognosis. It holds promise for aiding clinicians in assessing patient risks, guiding proactive prognosis management, and personalizing treatment, including targeted therapy or immunotherapy with checkpoint inhibitors. However, the disparities in sample sizes between normal and tumor specimens in this study necessitate further research to mitigate the variability brought on by sample size limitations. While the study confirms the impact of CPA4 on endometrial cancer cells, the intrinsic mechanisms by which CPA4 promotes the disease's development remain unclear. Future studies with larger sample sizes and in-depth pathway enrichment analyses are essential. Prospective studies and multifactorial diagnostic models are also needed to reduce bias and enhance the precision of prognosis and diagnosis, leveraging the full potential of biomarkers in conjunction with CPA4.