On chromosome 17, hsa_circ_0000745, containing coiled-coil and calponin homology domains, is formed through SPECC1 gene splicing. In gastric cancer patients, its expression is significantly reduced in blood and tumor tissues, with studies linking its levels to tumor differentiation [5]. We analyzed multiple cancer types to examine SPECC1 expression, its genetic changes, immune associations, prognosis, and regulatory networks in human cancers. KEGG analysis identified SPECC1-related pathways, including PI3K-AKT, cytokine-receptor interactions, and focal adhesion, all linked to cancer. PI3K-AKT regulates cell survival, growth, and apoptosis, often disrupted in cancerSPECC1 regulates the cytoskeleton and adhesion, aiding tumor survival and spread. The cytokine-receptor pathway controls immune responses in tumors. SPECC1 is linked to immune cell infiltration, especially TAMs and CD8 + T cells, suggesting its role in immune evasion and tumor growth through cytokine signaling. It also affects focal adhesion, aiding cytoskeleton stability and cell motility, which helps cancer cells migrate and invade. These pathways show SPECC1's key role in tumor growth, spread, and immune regulation, making it a promising therapeutic target.

Our study found abnormal SPECC1 expression in over half of all cancers. Most, like PAAD and BRCA, showed higher levels, while HCC had lower levels. SPECC1 was notably downregulated in COAD and UCEC, likely due to epigenetic changes like DNA methylation and histone modifications. The tumor microenvironment, immune cell infiltration, and stromal differences may suppress SPECC1 in COAD and UCEC. In COAD, high MSI affects genes related to immune response and cell structure, while hormonal and immune pathways in UCEC may lower SPECC1. Activation and mutations in the PI3K-AKT and WNT pathways likely contribute, along with epigenetic changes and tumor-specific factors.

SPECC1 had higher genetic variation in endometrial, sarcoma, and esophageal cancers. Gastric cancer showed reduced hsa_circ_0000745 expression, correlating with tumor differentiation. [5]. Studies show that tumor differentiation and venous infiltration in cervical cancer are linked to hsa_circ_0000745 expression, suggesting its role in cancer development [6, 7]. SPECC1 expression is linked to poor prognosis in multiple cancers, including lung, kidney, breast, and cervical cancer [8]. Few studies have explored hsa_circ_0000745 in malignant tumors, with no prognostic analyses in other cancers. SPECC1, with its varied expression in tissues and tumors, plays a key role in cancer progression through cytoskeletal dynamics, cell adhesion, migration, and immune modulationSPECC1 is a protein crucial for stabilizing microtubules and actin filaments, which are vital for cell structure and division. In cancer, disrupted cytoskeletal dynamics drive tumor progression, aiding in uncontrolled growth and metastasis. SPECC1 interacts with actin and microtubules to regulate cell movement and adhesion, making it key in cancer invasion by helping tumor cells detach and spread.

TMB is a promising biomarker for predicting cancer outcomes and guiding immunotherapy in precision medicine [9, 10]. TMB may serve as a biomarker to improve immunotherapy for colorectal and non-small-cell lung cancers, a recent study found [11]. TMB can also predict a pan-cancer patient's prognosis after treatment. MSI is a key biomarker for immune checkpoint inhibitors (ICIs) [12,13,14]. High-frequency MSI in colorectal cancer reliably indicates prognosis and clinical features [15]. Our study found a strong link between infiltrating cells, immune checkpoint genes (PDCD1, CTLA-4, macrophages), and SPECC1 expression. This suggests SPECC1 levels impact TMB and MSI in cancer, influencing a patient's response to immune checkpoint inhibitor therapy. Cyclic RNAs function in miRNA sponge-like adsorption [16], endogenous mRNA competition [17], interactions with RNA-binding proteins to regulate translation [18], and translation into biologically active peptides [19], among others. The most extensively studied function is the sponge-like adsorption of miRNAs. The most widely studied function is miRNA sponge-like adsorption, where cyclic RNAs isolate miRNAs, preventing them from binding to target genes. This regulation of target proteins in tumors can have cancer-suppressive or cancer-promoting effects. Recent evidence has also highlighted SPECC1's role in modulating the tumor immune microenvironment. Our study found that higher SPECC1 expression is linked to more tumor-associated macrophages (TAMs) and fewer CD8 + T cells, suggesting a suppressed immune response. TAMs promote tumor growth by aiding angiogenesis and suppressing immunity.

Conversely, the reduction of cytotoxic CD8 + T cells in SPECC1-high tumors suggests that SPECC1 may facilitate immune evasion, a critical step in cancer progression. Moreover, SPECC1 has been shown to impact drug sensitivity. Cell lines with higher SPECC1 expression exhibit increased sensitivity to chemotherapeutic agents such as doxorubicin and docetaxel, which suggests that SPECC1 may influence the efficacy of treatment. This observation has important clinical implications, as it could guide personalized therapy decisions based on SPECC1 expression levels in different cancer types.

A previous study identified SPECC1 as a differentially expressed circular RNA for in-depth investigation. Suppression of SPECC1 expression significantly reduced cervical cancer cell invasion, migration, proliferation, and tumorigenicity in nude mice, suggesting a pro-cancer role for SPECC1 in cervical cancer development. SPECC1 is suggested to function as a pro-cancer factor in cervical cancer development. The influence of hsa-circ I-0000745 on the biological behavior of cervical cancer cells suggests that p38 MAPK, B-catenin, Vimentin, P. RAS, and E. cadherin may be SPECC1 targets [20]. In other cancers, cyclic RNAs regulate breast cancer cells via the PI3K-AKT pathway, promoting tumor progression [21]. Beyond miRNA adsorption, another study found that the cyclic RNA FECR1 enhances cancer cell invasiveness [22]. Our findings suggest that SPECC1-related genes are widely expressed in the collagen-containing extracellular matrix, cell-substrate interface, focal adhesion, and PI3K-AKT signaling pathway. Genes involved in cell-substrate junctions are essential for cytokine-receptor interactions and the PI3K-AKT signaling pathway. Our initial research across various cancer types revealed distinct SPECC1 expression patterns between normal and cancerous tissues, as well as a relationship between SPECC1 expression and patient prognosis. Our study indicates that SPECC1 is an independent prognostic factor for various cancer types. The level of SPECC1 expression in a tumor also influences its prognostic outcome. Further investigation is required to clarify SPECC1's precise role in different cancer types. Additionally, TMB, MSI, and immune cell infiltration were linked to SPECC1 expression across various cancer types. Tumor impact on immune response depends on its nature. These findings could clarify SPECC1's role in cancer development and metastasis, providing guidance for developing specialized and targeted immunotherapies. Overall, SPECC1 not only serves as a pan-cancer biomarker but also plays a functional role in driving cancer progression through its involvement in cellular adhesion, cytoskeletal organization, immune evasion, and drug sensitivity. Future studies should focus on further delineating the precise molecular mechanisms by which SPECC1 contributes to tumor biology and exploring its potential as a therapeutic target in cancer treatment.

Although our study provides comprehensive bioinformatics evidence linking SPECC1 expression to cancer progression, drug sensitivity, and immune regulation across multiple cancer types, it is important to acknowledge the lack of in vivo experimental validation. The findings are based on large datasets from publicly available sources such as TCGA, GTEx, and CCLE. While these datasets offer valuable insights into gene expression patterns and their potential clinical significance, in vivo studies are needed to confirm SPECC1's functional role in tumor biology. Future research should focus on in vivo experiments using animal models and patient-derived xenografts (PDX) to investigate the effects of SPECC1 knockdown or overexpression on tumor growth, metastasis, and chemotherapy response. Additionally, in vivo validation of the correlation between SPECC1 expression and immune cell infiltration, particularly tumor-associated macrophages and cytotoxic CD8 + T cells, could be performed using immunohistochemical analysis of tumor tissues. To establish SPECC1 as a therapeutic target, further in vivo and clinical validation is essential. Clinical trials could explore SPECC1 expression levels as predictive biomarkers for chemotherapy efficacy, particularly in cancers such as breast, pancreatic, and hepatocellular carcinoma, where SPECC1 is overexpressed. Additionally, targeted therapeutic strategies, including small molecule inhibitors or SPECC1-specific siRNA or CRISPR-Cas9 approaches, could be developed to modulate its activity. Given SPECC1's role in immune regulation, future studies should also assess its impact on immune checkpoint blockade therapies, investigating whether SPECC1 inhibition enhances the efficacy of PD-1/PD-L1 or CTLA-4 inhibitors in specific cancers. These research directions will help translate our bioinformatics findings into clinical applications, potentially leading to personalized therapeutic strategies that improve patient outcomes.