A Hidden “Promoter”: <i>Schistosoma japonicum</i> soluble egg antigen activates MAPK/PI3K-AKT pathways and inhibits autophagy to facilitate colorectal cancer

Schistosomiasis affects approximately 250 million people globally. Eggs deposited in the colon are the main culprits causing pathological damage, with soluble egg antigen (SEA) being the most significant pathogenic factor in schistosomiasis. Colorectal cancer (CRC) is the most common type of gastrointestinal carcinoma. The colorectum is a common organ affected by both CRC and schistosomiasis. Clinical reports have demonstrated a correlation between the onset and poor prognosis of CRC and <i>Schistosoma japonicum</i> infection. However, there is still a lack of experimental evidence regarding the effect of schistosomiasis japonica on CRC. In this study, we found that <i>S. japonicum</i> SEA promoted the proliferation of CRC cells in a dose-dependent manner and upregulated the expression of Ki67. Moreover, SEA enhanced the migration and epithelial-mesenchymal transition of CRC cells. RNA sequencing analysis revealed that SEA activated the MAPK and PI3K-AKT signaling pathways while inhibiting autophagy in HCT116 cells, findings that were subsequently validated by Western blotting. In the murine xenograft model, SEA promoted tumor growth, increased the expression of Ki67 and Vimentin, and activated the MAPK and PI3K-AKT signaling pathways in tumor tissues. Overall, our findings demonstrate that <i>S. japonicum</i> SEA accelerates the malignant development of CRC both <i>in vitro</i> and <i>in vivo</i>, which is linked to the suppression of autophagy and the activation of MAPK and PI3K-AKT signaling. This is the first demonstration that the <i>S. japonicum</i> SEA participates in the induction of CRC-related signaling pathways, thus providing experimental evidence for the impact of schistosomiasis in endemic areas on CRC.IMPORTANCEThis research provides crucial experimental evidence bridging clinical observations and molecular mechanisms in schistosomiasis-associated colorectal cancer (CRC). For the first time, we demonstrate that <i>S. japonicum</i> soluble egg antigen (SEA) accelerates CRC malignancy both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, SEA activates the key oncogenic MAPK and PI3K-AKT signaling pathways while inhibiting autophagy. These findings establish a functional link between a specific parasitic factor and host cancer-driving pathways. This work strongly suggests that chronic exposure to SEA in endemic areas constitutes a defined biological risk factor for CRC. Ultimately, this study provides experimental evidence for elucidating the impact of <i>S. japonicum</i> infection on CRC and further deepens our understanding of the role of SEA in promoting tumor progression. Our study highlights the importance of schistosomiasis control as a potential strategy for CRC prevention in endemic regions.