The Role of RAB GTPases and Its Potential in Predicting Immunotherapy Response and Prognosis in Colorectal Cancer

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.

RAB6B is a potential prognostic marker and correlated with the remolding of tumor immune microenvironment in hepatocellular carcinoma

“…Prior study has shown that high RAB6B expression promoted cell proliferation and the cell cycle G1/S phase transition through AKT/ JNK signaling pathways in gastric cancer (Zhao et al, 2020). By contrast, RAB6B was low expressed in pancreatic and colorectal cancers, and correlated with poorer prognosis in patients (Anand et al, 2020;Jiang et al, 2022). These results suggested that RAB6B may play specific roles in different TME.…”

Proteomics-Derived Biomarker Panel Facilitates Distinguishing Primary Lung Adenocarcinomas With Intestinal or Mucinous Differentiation From Lung Metastatic Colorectal Cancer

“…NARR, an isoform of RAB34, is small GTPases involved in protein transport and is associated with many cancers ( 59 , 60 , 61 , 62 , 63 , 64 ). For example, recent studies have found that RAB34 was downregulated in CRC ( 63 ) but upregulated in the non-small cell lung cancer ( 64 ) when compared with nonmalignant tissues. RAB34 expression is also linked with poor prognosis in CRC ( 63 ).…”

Exosomal miR-10527-5p Inhibits Migration, Invasion, Lymphangiogenesis and Lymphatic Metastasis by Affecting Wnt/β-Catenin Signaling via Rab10 in Esophageal Squamous Cell Carcinoma

“…Further investigation demonstrated that Rab10 is a direct target gene of miR-10527-5p. Rab10, a member of the small GTPase family, 40 has been identified as an oncogene in various cancers, such as breast cancer, osteosarcoma, and ESCC, and it participates in tumor metastasis by affecting different processes, including invasion, migration, EMT, immune evasion and chemoresistance. [41][42][43] In our study, Rab10 was found to be significantly elevated in LNM + ESCC tissues and tended to be associated with poor prognosis in ESCC patients.…”