Globally, the incidence and mortality rates of colorectal cancer (CRC) continue to remain high. In 2020, worldwide statistics reported almost two million newly diagnosed cases and over 900,000 deaths, representing 10.0% and 9.4% of cancer incidence and mortality, respectively. Colorectal cancer ranks as the third and second most common malignant tumor in terms of incidence and mortality, respectively. Furthermore, there appears to be a gradual decrease in the age of onset (Sung et al., 2021). Accounting for approximately 80%–90% of all primary liver malignancies, primary hepatocellular carcinoma (HCC) ranks as the third most common cause of cancer-related deaths globally (Peeters and Dekervel, 2023). These two diseases seriously threaten the health of mankind.

Dual primary carcinoma is a type of multiple malignant tumors. It can be classified into synchronous carcinoma (SC) and metachronous carcinoma (MC), based on the time interval between the onset of the diseases, typically divided by using 6 months as the cutoff point (Park et al., 2005). In a study for 40 cases who confirmed by pathological examination as CRC combined with PHC double primary carcinoma suggested that both CRC and HCC belong to abdominal malignancies. However, since the liver is the main target organ for CRC hematogenous metastasis, imaging physicians tend to confuse the characteristics of CRC and HCC metastatic liver cancer in the identification of the characteristics of intrahepatic occupying lesions, as well as the coexistence of CRC and HCC liver metastases, it is difficult to make accurate diagnosis based on imaging data before surgery (Zhiping et al., 2023). Therefore, it is necessary to identify potential biomarkers and therapeutic targets for these coexisting metastases by other diagnostic tools.

Currently, there have been numerous reports of double primary cancer, where CRC is combined with HCC, both domestically and internationally. Approximately 15%–25% of patients with colorectal cancer present with synchronous liver metastases at the time of initial presentation (Kianmanesh et al., 2007; Engstrand et al., 2018). A retrospective cohort study demonstrated the risk for HCC with CRC, especially in patients with rectal cancer (Lee et al., 2015). A recent study showed that deoxycholic acid (DCA), a secondary bile acid known to cause DNA damage, may return to the liver through enterohepatic circulation and provoke the senescence-associated secretory phenotype in hepatic stellate cells, which in turn secretes pro-inflammatory and tumor-promoting factors in the liver and facilitates dual primary tumor development (Yoshimoto et al., 2013). Further studies are needed to explore this interesting phenomenon. However, few studies have been conducted to investigate the common pathway underlying these two diseases. The development of CRC and HCC has been linked to multiple altered signaling pathways. In CRC, about ninety percent of all tumors have a mutation in a key regulatory factor of the Wnt/β-catenin pathway, with APC or CTNNB1 being the most common affected genes. This mutation leads to the activation of the Wnt/β-catenin pathway (Wanitsuwan et al., 2008). HCC is also characterized by early genetic alterations in telomerase reverse transcriptase promoter (TERTp) and CTNNB1 genes and immune cell activation in the tumor microenvironment (Ambrozkiewicz et al., 2022).

The aim of this research is to discover hub genes related to the pathogenesis of colorectal carcinoma and hepatocellular carcinoma, and explore the potential common pathogenesis between the two diseases. To achieve this goal, two gene expression data sets (GSE90627 and GSE45267) were analyzed using comprehensive bioinformatics and enrichment analysis. The common differentially expressed genes (DEGs) and their functions in CRC and HCC were identified. Moreover, a protein-protein interaction (PPI) network was constructed to analyze gene modules and identify hub genes using the STRING database and Cytoscape software. The transcription factors of the hub genes were also analyzed and their expression was verified. Through this process, important hub genes and their prognostic value were analyzed. The discovery of these hub genes is expected to provide new insights into the biological mechanisms of CRC and HCC, particularly their shared transcription features.

Metastasis is thought to occur in multiple stages, starting with the primary tumor’s ability to survive in the bloodstream and enter the parenchyma of remote organs. Once there, the cancer cells must adapt to the foreign environment and grow into secondary tumors (Steeg, 2006). The ability to complete the metastatic process is thought to be limited to only a small number of tumor cells. Furthermore, the emergence of metastases occurs at varying rates, with certain organ sites being preferred depending on the type of cancer (Nguyen and Massagué, 2007; Chen et al., 2023; Liu et al., 2023). As a result, primary tumor cells and their metastatic descendants are expected to differ significantly in terms of tumor biology. While numerous genes associated with metastasis have been identified, their involvement in the development of metastasis in different types of tumors, their role in organ-specific metastasis, and how they drive progression are not yet fully understood (Sethi and Kang, 2011; Valastyan and Weinberg, 2011).

In recent years, the study and understanding of the tumor microenvironment has become as important as the modulation of cancer cell progression itself (Pavlova and Thompson, 2016; Sun et al., 2021; Ng et al., 2022). CRC and HCC are both highly resistant to therapy. Despite being the third leading cause of cancer-related death worldwide, HCC is not the only cancer type that is difficult to treat. Over the past decade, overall survival rates for CRC patients have not shown significant improvement (Torre et al., 2012; Fitzmaurice et al., 2015). Despite progress in available therapies, the survival rates of patients with CRC and HCC have only seen modest improvements. This is largely due to the lack of effective early detection methods and reliable prognostic indicators (Ye et al., 2015).

CRC and HCC might have overlapping pathogenic pathways. The mechanism of increased risk for multiple malignant tumors in patients with CRC is uncertain. Some etiologies, including underlying genetic background, lifestyle, and environmental risk factors, are involved with the development of cancers (Hemminki et al., 2001). In this study, we identified 148 overlapping DEGs in both, of which 10 were common hub genes, including CDK1, KIF11, CDC20, CCNA2, TOP2A, CCNB1, NUSAP1, BUB1B, ASPM and MAD2L1. According to our GO and KEGG Pathway enrichment analysis, the cell cycle regulation play an important role in these two diseases. Of these hub genes, CDK1, a kinase that acts on the core of the cell cycle, attracted our attention (Nurse and Bissett, 1981). The CDK1/cyclin B1 (CCNB1) complex is crucial not only for mitochondrial activities during cell cycle progression but also for the development of adaptive resistance in tumors (Wang et al., 2014; Liu et al., 2015). Proper regulation of cell proliferation is crucial for preventing the development of cancer as it plays a critical role in both the initiation and promotion of tumors (López-Sáez et al., 1998). The regulation and control of cancer cell proliferation are complex processes that involve numerous mechanisms, including those that accelerate or disrupt the cell cycle. Tumor suppressor pathways have been identified as negative regulators in signal transduction systems that lead to cell cycle arrest at various checkpoints (Mori et al., 1999). Significantly enriched differentially expressed genes that are positively associated with CDK1 were identified through publicly available expression profiles and KEGG and GO analyses. These genes were found to be involved in DNA replication, mismatch repair, and cell cycle pathways, indicating that CDK1 may interact with factors in these pathways to exert its effects.

Multiple studies have suggested that CDC20 plays a role in the oncogenesis of human cancers. Elevated CDC20 expression has been linked to clinicopathological features in various types of human cancers (Jeong et al., 2022). Elevated expression of CDC20 was observed in cell lines of colorectal cancer, with levels positively correlated with late clinical-stage, metastasis, and lower survival rates. These findings suggest that CDC20 could serve as a crucial diagnostic and prognostic biomarker for human colorectal cancer (Wu et al., 2013). In a previous study, CDC20 was found to be upregulated in 68% of HCCs compared to adjacent normal tissues. Notably, the overexpression of CDC20 was significantly associated with sex, tumor differentiation, and TNM stage (Li et al., 2014). These findings suggest that CDC20 may serve as a promising therapeutic target for HCC, although further investigations are needed to confirm the clinical implications of CDC20 suppression in the treatment of liver cancer.

Exploring the biological basis for differences in the prognostic value of hub genes in CRC and HCC is a key goal of this study. Of all the common hub genes, TOP2A is the most noteworthy because it has divergent survival outcomes in these two diseases. TOP2A is closely linked to cell proliferation and is therefore a promising therapeutic target for diseases characterized by increased cellular proliferation (Kim et al., 2015). TOP2A, a highly expressed gene in various types of carcinomas, is valuable in diagnosing cancer, monitoring disease progression, and predicting prognosis. In a previous study, TOP2A expression was assessed in 490 CRC tissues, and it was found that overexpression of TOP2A was associated with a lower T stage, lower N stage, and lower recurrence rate (Hua et al., 2015). Moreover, the study suggested that ZNF148 and TOP2A reciprocally regulate each other in CRC through the ceRNA mechanism involving miR101, miR144, miR335, and miR365, which is crucial in the regulation of cell proliferation in CRC (Gao et al., 2017). However, previous results show that TOP2A is involved in the development of liver cancer (Panvichian et al., 2015). In their report, Liu et al. demonstrated that MDM4 and TOP2A have a post-translational interaction, leading to their mutual upregulation and increased stability of TOP2A protein. This interaction also inhibits the p53 pathway and promotes tumor cell proliferation (Liu et al., 2019). In previous studies, the differential expression of MAD2L1 in many tumors was analyzed using the TIMER2.0 database (Chen et al., 2020). For CRC, the higher expression of MAD2L1 has been observed to counteract the repressive impact of miR-515-5p overexpression on the proliferation of colorectal cancer cells, as well as the induction of apoptosis and G1-phase detainment (Ding et al., 2022). However, survival analysis showed high expression of MAD2L1 in HCC correlated with shorter OS. This finding was also validated in other datasets which confirmed that high expression of MAD2L1 was an independent risk factor for OS in patients with HCC (Chen et al., 2022).

Current research is still inadequate to fully elucidate the distinct prognostic value of these hub genes in these two cancers, and further extensive investigations and clinical trials are warranted. The information on KEGs provides valuable insights into the pathogenesis of CRC and HCC, and could potentially aid in the development of targeted therapeutic approaches. Intriguingly, findings from a study on dual primary cancer involving both CRC and HCC indicated that the type, age of onset, interval of onset, and presence or absence of mutations in CRC-related genes in the first primary cancer did not significantly impact the prognosis of patients with dual primary cancer (Zhiping et al., 2023).

We analyzed related TFs and verified their expression levels in the original dataset, in addition to exploring hub genes. Our study provides potential directions for understanding the molecular mechanism of CRC complicated by HCC. Unlike previous studies (Cheng et al., 2020; Pan et al., 2022), we focused on common hub genes and related TFs due to the strong genetic similarity between the two cancers. To identify key nodes, we constructed a complex interaction network using their common DEGs. This comprehensive bioinformatics method has proven reliable in various diseases (Fang et al., 2020).

Advanced bioinformatics methods have not been extensively used to explore the shared molecular mechanisms between CRC and HCC. However, our research has some limitations, including its retrospective nature, which necessitates external validation of our findings. Additionally, the function of the identified hub gene requires further in vitro validation, which will be the focus of our future work. Nonetheless, our study has notable strengths. Given the high incidence of comorbidity between CRC and HCC, we identified common DEGs, hub genes, and TFs between these two cancers for the first time, thus providing further insights into their underlying mechanisms.

Our study focused on identifying the shared DEGs in CRC and HCC. Furthermore, we conducted enrichment analysis and PPI network analysis. Our results revealed that CRC and HCC share numerous pathogenic pathways, which may be regulated by certain hub genes. This study presents novel perspectives that can aid in exploring the molecular mechanisms underlying the development of these two cancers.