Abstract
Background: Colorectal cancer (CRC) is the third most common cancer worldwide, in which aberrant activation of the RAS signaling pathway appears frequently. RAB proteins (RABs) are the largest Ras small GTPases superfamily that regulates intracellular membrane trafficking pathways. The dysregulation of RABs have been found in various diseases including cancers. Compared with other members of Ras families, the roles of RABs in colorectal cancer are less well understood. Methods: We analyzed the differential expression and clinicopathological association of RABs in CRC using RNA sequencing and genotyping datasets from TCGA samples. Moreover, the biological function of RAB17 and RAB34 were investigated in CRC cell lines and patient samples. Results: Of the 62 RABs we analyzed in CRC, seven (RAB10, RAB11A, RAB15, RAB17, RAB19, RAB20, and RAB25) were significantly upregulated, while six (RAB6B, RAB9B, RAB12, RAB23, RAB31, and RAB34) were significantly downregulated in tumor tissues as compared to normal. We found that the upregulated-RABs, which were highly expressed in metabolic activated CRC subtype (CMS3), are associated with cell cycle related pathways enrichment and positively correlated with the mismatch repair (MMR) genes in CRC, implying their role in regulating cell metabolism and tumor growth. While, high expression of the downregulated-RABs were significantly associated with poor prognostic CRC mesenchymal subtypes (CMS4), immune checkpoint genes, and tumor infiltrating immune cells, indicating their role in predicting prognosis and immunotherapy efficacy. Interestingly, though RAB34 mRNA is downregulated in CRC, its high expression is significantly associated with poor prognosis. In vitro experiments showed that RAB17 overexpression can promote cell proliferation via cell cycle regulation. While, RAB34 overexpression can promote cell migration and invasion and is associated with PD-L1/PD-L2 expression increase in CRC cells. Conclusions: Our study showed that RABs may play important roles in regulating cell cycle and immune-related pathways, therefore might be potential biomarkers in predicting prognosis and immunotherapy response in CRC.
Highlights
Colorectal cancer (CRC) is the third most prevalent cancer worldwide (Siegel et al, 2020; Siegel et al, 2021)
The mutation and deep deletion alteration occupied a higher proportion in downregulatedRABs, which may contribute to their downregulation at transcriptional level (Figure 1C)
We found that a high level of the upregulated-Ras-associated binding proteins (RABs) was significantly associated with the metabolic CMS3 subtype (Figure 2A), implying their involvement in the epithelial and metabolic dysregulation
Summary
Colorectal cancer (CRC) is the third most prevalent cancer worldwide (Siegel et al, 2020; Siegel et al, 2021). Deregulation of RABs has been reported in several diseases, including various cancers (Sun et al, 2018; Ganga et al, 2021). They function either as an oncogene or tumor suppressors depending on cancer types. The roles of RABs in colorectal cancer are less-well understood. Colorectal cancer (CRC) is the third most common cancer worldwide, in which aberrant activation of the RAS signaling pathway appears frequently. RAB proteins (RABs) are the largest Ras small GTPases superfamily that regulates intracellular membrane trafficking pathways. Compared with other members of Ras families, the roles of RABs in colorectal cancer are less well understood
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