Abstract
BackgroundThe small GTPase Ran is upregulated in multiple cancers and fundamental for cancer cell survival and progression, but its significance and molecular mechanisms in colorectal cancer (CRC) remain elusive.MethodsRan expression was detected in CRC cell lines and tumour tissues. In vitro and in vivo functional assays were performed to examine the effects of Ran on cell proliferation and metastasis. The pathways and effectors regulated by Ran were explored by an unbiased screening. Bioinformatics prediction and experimental validation were used to identify the miRNA regulator for Ran.ResultsRan expression was frequently increased in metastatic CRC cells and tissues, especially in metastatic tissues. The upregulation of Ran correlated with poor CRC patient prognosis. Ran silencing reduced proliferation and metastasis of CRC cells both in vitro and in vivo. Ran regulated the expression of EGFR and activation of ERK and AKT signalling pathways. miR-802 was identified as an upstream regulator of Ran and miR-802 overexpression resulted in antiproliferative and antimetastatic activities.ConclusionOur study demonstrates the oncogenic roles and underlying mechanisms of Ran in CRC and the novel miR-802/Ran/EGFR regulatory axis may provide potential biomarkers for the treatment of CRC.
Highlights
The small GTPase Ran is upregulated in multiple cancers and fundamental for cancer cell survival and progression, but its significance and molecular mechanisms in colorectal cancer (CRC) remain elusive
We found that elevated thioredoxin-like protein 2 (Txl-2) was strongly correlated with histological grade and CRC patient prognosis and demonstrated that the overexpression of Txl-2 promoted cell invasion and metastasis through its interaction with the GTPase Ran.[4]
We found that Ran is significantly upregulated in CRC cells and tissues, especially in metastatic tissues, and that the upregulation of Ran correlates with poor CRC patient prognosis
Summary
The small GTPase Ran is upregulated in multiple cancers and fundamental for cancer cell survival and progression, but its significance and molecular mechanisms in colorectal cancer (CRC) remain elusive. Ran belongs to the Ras superfamily of GTPases, which act as molecular switches that are turned on by GTP binding and off by GTP hydrolysis to GDP.[5] Ran has been shown to be involved in multiple cellular processes, including nucleocytoplasmic transport, assembly of the mitotic spindle, the regulation of cell cycle progression, and formation of the nuclear envelope.[6] Emerging evidence has demonstrated that Ran is often expressed at high levels in various cancers and that these aberrant expression levels are associated with the increased aggressiveness of cancer cells and a poor patient prognosis.[7] In pancreatic cancer, elevated Ran was found to promote proliferation and reduced apoptosis by regulating the expression of Survivin and cell cycle proteins.[8] In ovarian cancer, overexpressed Ran was correlated with poor patient survival and enhanced cell invasion by increasing the membrane targeting and stabilisation of RhoA.[9] We previously found that Ran is highly expressed in CRC tissues and positively correlated with tumour differentiation, local invasion and metastasis. The expression patterns of Ran in several cancer types have been determined, the causes of its overexpression have not yet been fully explored
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