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Abstract
Background Gastric cancer (GC) stands out as a significant global threat, while resistance to therapeutic agents poses a formidable challenge. Notably, the MCM10 protein is pivotal in initiating DNA replication, holding promise in mediating acquired chemotherapy resistance. This work aims to investigate the driving roles of MCM10 in GC.
Methods The expression pattern of MCM10 and its clinical relevance in GC patients was investigated by adopting single-cell RNA-seq data and in-house GC tissue microarray. The oncogenic roles of MCM10 were demonstrated by bioinformatic analysis and functional assays, including monolayer colony formation, cell invasion, sphere formation, and GC patient-derived organoid (PDO) growth. The regulation of MCM10 by YAP1-TEAD4 complex was identified by luciferase reporter assay and rescue assays.
Results MCM10 prevailed among MCM family proteins with the highest expression level in GC cell lines. The activation of MCM10 was observed in multiple datasets, and a poorer prognosis was predicted. Knocking down MCM10 attenuated the malignancy of GC cells and the size of PDOs (IDDF2024-ABS-0392 Figure 1 (I-K)). Bioinformatic analysis highlighted the correlation of MCM10 with DNA replication and repair processes. The predicted regulation was then validated by the expression alteration of cell cycle regulators in MCM10-deleted GC cells (IDDF2024-ABS-0392 Figure 2 (A-K)). Furthermore, MCM10 was upregulated in cisplatin-resistant GC cells. Deletion of MCM10 led to DNA damage and decreased cell stemness, as indicated by increased DNA damage repair activity, reduced expression of stemness markers, and decreased formation of cell line-derived spheroids (IDDF2024-ABS-0392 Figure 3 (A-J)). The relationship between MCM10 and TEAD4 was identified by multiple transcriptome analysis. TEAD4 knocking down directly led to the MCM10 downregulation and the deactivation of the cell cycle. Overexpressing TEAD4 in MCM10 deleted cells failed to rescue the attenuated cell carcinogenic activities (IDDF2024-ABS-0392 Figure 4 (A-I)). Hematoporphyrin was screened out from 4491 candidate drugs to be the best inhibitor for MCM10 (IDDF2024-ABS-0392 Figure 5 (A-D)).
Conclusions The hyperactivation of MCM10 plays a crucial role in gastric tumorigenesis by facilitating the DNA repair process and cancer cell stemness acquisition. This study elucidated the oncogenic mechanism of a vital effector in YAP1 signaling, suggesting a promising target for overcoming chemotherapy resistance in GC patients.