Currently, rectal cancer remains one of the most prevalent malignant tumors worldwide, with its incidence and mortality rates on the rise. Epidemiological studies have indicated that risk factors associated with rectal cancer include a high-fat diet, long-term chronic inflammation, and genetic factors [15–17]. In our country, rectal cancer exhibits high incidence and mortality rates, particularly in rural areas, and its growth rate is expedited. Various factors, such as tumor stage, histological grade, and lymph node metastasis influence the prognosis of rectal cancer. Advances in diagnostic and therapeutic techniques have significantly improved the prognosis of patients with early rectal cancer. Regrettably, due to the current national conditions and limited health awareness among the population, some patients in our country are diagnosed with advanced rectal cancer during their initial visit [18–21]. For these cases, neoadjuvant therapy is recommended, which offers the possibility of avoiding permanent colostomy [22–24]. However, while some patients benefit from neoadjuvant therapy, others often experience disease progression with no discernible effect from the treatment [25–27]. To address this issue, we must develop more accurate individual evaluation and treatment plans, construct predictive models, and identify targets for neoadjuvant therapy for advanced low rectal cancer. Achieving these objectives is currently the primary focus of research.
As we all know, rectal cancer represents a prevalent malignant tumor within the digestive tract, characterized by a multifactorial, multistep, and intricate pathogenesis. This process involves the aberrant regulation of signaling pathways and the crucial role of immune infiltration. At the molecular biology level, dysregulation of various signaling pathways, such as Wnt, MAPK, and PI3K/Akt, results in uncontrolled tumor cell proliferation and impaired apoptotic mechanisms, thereby exacerbating the progression of rectal cancer [28–30]. Furthermore, these dysregulated signaling pathways contribute to tumor invasion and migration, providing a molecular basis for metastasis.
Concurrently, investigating immune infiltration in the tumor microenvironment has emerged as a new research focus in rectal cancer. The level of immune cell infiltration, particularly the ratio and activity of T lymphocytes and macrophages, significantly correlates with the prognosis of rectal cancer patients. These immune cells not only directly eliminate tumor cells but also influence tumor growth rates and the response to radiotherapy through the release of cytokines. Therefore, a comprehensive exploration of the interactions between signaling pathways and immune infiltration in rectal cancer, along with their regulatory mechanisms, holds significant importance in unraveling the disease's pathogenesis, devising innovative therapeutic approaches, and improving patient prognosis. Meanwhile, immune cells such as CD8 + T cells, CD4 + T cells, and macrophages play a significant role in the progression and prognosis of rectal cancer [31, 32]. The extent of immune cell infiltration can also serve as an indicator of how well rectal cancer will respond to radiotherapy and chemotherapy 33–35. In our study, we conducted a comprehensive analysis by gathering information from various public databases, conducting a risk assessment, and independent prognostic analysis while considering multiple clinical indicators, we observed that the external datasets verified the robustness of our prognostic model, as they consistently demonstrated significantly different overall survival outcomes between the high-risk and low-risk groups. This consistency in survival predictions across multiple datasets strengthens the reliability and generalizability of our model. Additionally, we employed expression profiling to conduct a single-cell-level analysis of rectal cancer-associated sample tissues to provide evidence, the single-cell level expression analysis of the model genes provides a comprehensive and detailed view of their expression profiles and cellular heterogeneity within LARC. Understanding the cell type-specific expression, subpopulations, and co-expression patterns of these genes can aid in deciphering their functional significance and potential as therapeutic targets or biomarkers. Lastly, we explored the ceRNA network of disease gene expression level and model gene, our ceRNA network analysis provides insights into the regulatory interactions and potential functional roles of the model genes in rectal cancer. The identification of miRNA-mRNA interactions and their involvement in the ceRNA network offers a deeper understanding of the regulatory landscape in rectal cancer and may open new avenues for targeted therapeutic interventions.
After conducting statistical analysis, we were able to establish a significant correlation between comprehensive prediction models of four specific genes and the expression levels of various disease-related genes. Through the utilization of our newly developed predictive model and the identification of specific genes of interest, it is now possible to perform an initial evaluation for patients diagnosed with low-grade progressive rectal cancer who require neoadjuvant therapy. This evaluation is designed to reduce the risks of drug toxicity and tumor progression, ultimately enabling personalized and precise treatment for individuals with low-grade progressive rectal cancer.