Regulation of the small GTPase Ran by miR-802 modulates proliferation and metastasis in colorectal cancer cells

Abstract

Background 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. Methods Ran 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. Results Ran 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. Conclusion Our 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.

A new candidate oncogenic lncRNA derived from pseudogene WFDC21P promotes tumor progression in gastric cancer

“…Ran was reported to activate the EMT process and various metastasis-related signaling pathways, such as the Akt pathway, Ras pathway, and β-catenin pathway [ 20 , 21 ]. The oncogenic functions of Ran have been confirmed in colorectal cancer, breast cancer, ovarian cancer, and other solid tumors [ 22 – 25 ]. In GC, Ran was found upregulated and expected to be an immune recognition site molecule [ 26 ].…”

Dysfunction of miR‐802 in tumors

“…In vitro experiments also further showed that miR-802 promoted the proliferation of lung cancer cells. 35 The abnormal expression of miR-802 has been confirmed in the tumor tissues or tumor cells of 15 cancers, including TSCC, 4 OSCC, 5,6 LSCC, 8 GC, [9][10][11] CRC, [12][13][14] PC, [30][31][32] HCC, [22][23][24][25] PCa, 2,33 bladder urothelial cancer, 26 BC, 15,16 CC, [17][18][19] EOC, 20 lung cancer, [34][35][36] osteosarcoma, 27,28 and melanoma. 21 To note, the abnormal expression of miR-802 in ESCC 7 and cholesteatoma 29 has only been confirmed in tumor cells.…”

“…Subsequent experiments further revealed that miR-802 expression can regulate a series of cell behaviors, including cell proliferatio n, 2,[7][8][9]11,[13][14][15]18,[20][21][22][24][25][26]28,29,31,[33][34][35] invasion, 4,6,[11][12][13][14]17,[19][20][21]33,34,36 metastasis, 2,6,7,[11][12][13][14]17,20,21,25,26,33,34,36 apoptosis, [8][9][10]13,...…”

“…Some studies have also confirmed the tumor suppressor effect of miR‐802 in mouse models. Existing studies have found that the expression of miR‐802 is decreased in at least 10 cancers, including TSCC, 4 OSCC, 5 , 6 ESCC, 7 LSCC, 8 GC, 9 , 10 , 11 CRC, 12 , 13 , 14 BC, 15 , 16 CC, 17 , 18 , 19 EOC, 20 and melanoma. 21 It is worth noting that the direction of abnormal expression of miR‐802 in the other 4 tumors is inconsistent.…”

“…Subsequent experiments further revealed that miR‐802 expression can regulate a series of cell behaviors, including cell proliferation, 2 , 7 , 8 , 9 , 11 , 13 , 14 , 15 , 18 , 20 , 21 , 22 , 24 , 25 , 26 , 28 , 29 , 31 , 33 , 34 , 35 invasion, 4 , 6 , 11 , 12 , 13 , 14 , 17 , 19 , 20 , 21 , 33 , 34 , 36 metastasis, 2 , 6 , 7 , 11 , 12 , 13 , 14 , 17 , 20 , 21 , 25 , 26 , 33 , 34 , 36 apoptosis, 8 , 9 , 10 , 13 , 18 , ...…”