Gene Summary

Gene:RAB25; RAB25, member RAS oncogene family
Aliases: CATX-8, RAB11C
Summary:The protein encoded by this gene is a member of the RAS superfamily of small GTPases. The encoded protein is involved in membrane trafficking and cell survival. This gene has been found to be a tumor suppressor and an oncogene, depending on the context. Two variants, one protein-coding and the other not, have been found for this gene. [provided by RefSeq, Nov 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:ras-related protein Rab-25
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: RAB25 (cancer-related)

Wang J, Zhou P, Wang X, et al.
Rab25 promotes erlotinib resistance by activating the β1 integrin/AKT/β-catenin pathway in NSCLC.
Cell Prolif. 2019; 52(3):e12592 [PubMed] Related Publications
OBJECTIVES: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has significant therapeutic efficacy in non-small-cell lung cancer (NSCLC) patients. However, acquired resistance is inevitable and limits the long-term efficacy of EGFR-TKI. Our study aimed to investigate the role of ras-associated binding protein 25 (Rab25) in mediating EGFR-TKI resistance in NSCLC.
MATERIALS AND METHODS: Rab25 expression in NSCLC patients was measured by immunohistochemical staining. Western blotting was used to analyse the expression of molecules in the Rab25, EGFR and Wnt signalling pathways. Lentiviral vectors were constructed to knock in and knock out Rab25. The biological function of Rab25 was demonstrated by cell-counting kit-8 and flow cytometry. The interaction between Rab25 and β1 integrin was confirmed by co-immunoprecipitation.
RESULTS: Rab25 overexpression induced erlotinib resistance, whereas Rab25 knockdown reversed this refractoriness in vitro and in vivo. Moreover, Rab25 interacts with β1 integrin and promotes its trafficking to the cytoplasmic membrane. The membrane-β1 integrin induced protein kinase B (AKT) phosphorylation and subsequently activated the Wnt/β-catenin signalling pathway, promoting cell proliferation. Furthermore, high Rab25 expression was associated with poor response to EGFR-TKI treatment in NSCLC patients.
CONCLUSIONS: Rab25 mediates erlotinib resistance by activating the β1 integrin/AKT/β-catenin signalling pathway. Rab25 may be a predictive biomarker and has potential therapeutic value in NSCLC patients with acquired resistance to EGFR-TKI.

Yin C, Mou Q, Pan X, et al.
MiR-577 suppresses epithelial-mesenchymal transition and metastasis of breast cancer by targeting Rab25.
Thorac Cancer. 2018; 9(4):472-479 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MicroRNAs can act as both tumor suppressor genes and oncogenes and participate in cell proliferation, metastasis, and apoptosis. Low levels of miR-577 are found in several cancers, for example, thyroid carcinoma, glioblastoma, and hepatocellular carcinoma. The aim of this study was to investigate the effect of miR-577 on breast cancer (BC).
METHODS: The relative level of miR-577 in 120 BC tissues and cells was detected by real-time PCR. MDA-MB-231 cells with upregulated miR-577 and MCF-7 cells with downregulated miR-577 were established. Transwell invasion assays were used to examine the invasiveness of cells. Epithelial-mesenchymal transition (EMT) markers were evaluated by immunofluorescence and Western blot. Targeted combinations of miR-577 and Rab25 were analyzed by luciferase assays. Xenograft models were used to examine the effect of miR-577 on BC metastasis.
RESULTS: MiR-577 expression was significantly suppressed in BC tissues. Tumor size, tumor stage, and lymphatic metastasis were attributed to miR-577 expression. Moreover, miR-577 overexpression strongly inhibited the invasiveness and EMT of BC cells in vitro. MiR-577 directly regulated Rab25 in BC. Rab25 upregulation by miR-577 decreased the levels of E-cadherin and increased the levels of Vimentin. Notably, Rab25 knockdown inhibited BC invasion; however, an increase in Rab25 counteracted the invasive effect of miR-577 in BC.
CONCLUSION: Results indicated that miR-577 suppressed EMT by inhibiting Rab25 expression in BC. MiR-577 and Rab25 are considered potential targets of BC treatment.

Jeong BY, Cho KH, Jeong KJ, et al.
Rab25 augments cancer cell invasiveness through a β1 integrin/EGFR/VEGF-A/Snail signaling axis and expression of fascin.
Exp Mol Med. 2018; 50(1):e435 [PubMed] Free Access to Full Article Related Publications
The small GTP-binding protein Rab25 is associated with tumor formation and progression. However, recent studies have shown discordant effects of Rab25 on cancer cell progression depending on cell lineage. In the present study, we elucidate the underlying mechanisms by which Rab25 induces cellular invasion. We demonstrate that Rab25 increases β1 integrin levels and subsequent activation of EGFR and upregulation of VEGF-A expression, leading to increased Snail expression, epithelial-to-mesenchymal transition and cancer cell invasiveness. Strikingly, we identify that Snail mediates Rab25-induced cancer cell invasiveness through fascin expression and that ectopic expression of Rab25 aggravates metastasis of ovarian cancer cells to the lung. We thus demonstrate a novel role of a β1 integrin/EGFR/VEGF-A/Snail signaling cascade in Rab25-induced cancer cell aggressiveness through induction of fascin expression, thus providing novel biomarkers and potential therapeutic targets for Rab25-expressing cancer cells.

Gu Y, Zou YM, Lei D, et al.
Promoter DNA methylation analysis reveals a novel diagnostic CpG-based biomarker and RAB25 hypermethylation in clear cell renel cell carcinoma.
Sci Rep. 2017; 7(1):14200 [PubMed] Free Access to Full Article Related Publications
Clear-cell renal cell carcinoma (ccRCC) is a common aggressive urinary malignant tumor that cannot be easily diagnosed at an early stage. The DNA methylation occurs within promoter before precancerous lesion plays a pivotal role that could help us in diagnosing and understanding ccRCC. In this study, based on a whole-genome promoter DNA methylation profiling, we used shrunken centroids classifier method to identify a CpG-based biomarker that is capable of differentiating between ccRCC tumor and adjacent tissues. The biomarker was validated in 19 ccRCCs and three public datasets. We found that both CYP4B1 and RAB25 are downregulated with promoter hypermethylation and CA9 is upregulated with promoter hypomethylation, and we validated their mRNA differential expressions in 19 ccRCCs and 10 GEO datasets. We further confirmed that hypermethylated RAB25 is inversely correlated with its mRNA level. Log-rank test showed that ccRCC patients with low levels of CA9 promoter methylation had a higher survival rate. This reveals clinically a potential biomarker for use in early detection for ccRCC, and provides a better understanding of carcinogenesis.

Letellier E, Schmitz M, Ginolhac A, et al.
Loss of Myosin Vb in colorectal cancer is a strong prognostic factor for disease recurrence.
Br J Cancer. 2017; 117(11):1689-1701 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Selecting the most beneficial treatment regimens for colorectal cancer (CRC) patients remains challenging due to a lack of prognostic markers. Members of the Myosin family, proteins recognised to have a major role in trafficking and polarisation of cells, have recently been reported to be closely associated with several types of cancer and might thus serve as potential prognostic markers in the context of CRC.
METHODS: We used a previously established meta-analysis of publicly available gene expression data to analyse the expression of different members of the Myosin V family, namely MYO5A, 5B, and 5C, in CRC. Using laser-microdissected material as well as tissue microarrays from paired human CRC samples, we validated both RNA and protein expression of Myosin Vb (MYO5B) and its known adapter proteins (RAB8A and RAB25) in an independent patient cohort. Finally, we assessed the prognostic value of both MYO5B and its adapter-coupled combinatorial gene expression signatures.
RESULTS: The meta-analysis as well as an independent patient cohort study revealed a methylation-independent loss of MYO5B expression in CRC that matched disease progression. Although MYO5B mutations were identified in a small number of patients, these cannot be solely responsible for the common downregulation observed in CRC patients. Significantly, CRC patients with low MYO5B expression displayed shorter overall, disease-, and metastasis-free survival, a trend that was further reinforced when RAB8A expression was also taken into account.
CONCLUSIONS: Our data identify MYO5B as a powerful prognostic biomarker in CRC, especially in early stages (stages I and II), which might help stratifying patients with stage II for adjuvant chemotherapy.

Mitra S, Montgomery JE, Kolar MJ, et al.
Stapled peptide inhibitors of RAB25 target context-specific phenotypes in cancer.
Nat Commun. 2017; 8(1):660 [PubMed] Free Access to Full Article Related Publications
Recent evidence has established a role for the small GTPase RAB25, as well as related effector proteins, in enacting both pro-oncogenic and anti-oncogenic phenotypes in specific cellular contexts. Here we report the development of all-hydrocarbon stabilized peptides derived from the RAB-binding FIP-family of proteins to target RAB25. Relative to unmodified peptides, optimized stapled peptides exhibit increased structural stability, binding affinity, cell permeability, and inhibition of RAB25:FIP complex formation. Treatment of cancer cell lines in which RAB25 is pro-oncogenic with an optimized stapled peptide, RFP14, inhibits migration, and proliferation in a RAB25-dependent manner. In contrast, RFP14 treatment augments these phenotypes in breast cancer cells in which RAB25 is tumor suppressive. Transcriptional profiling identified significantly altered transcripts in response to RAB25 expression, and treatment with RFP14 opposes this expression profile. These data validate the first cell-active chemical probes targeting RAB-family proteins and support the role of RAB25 in regulating context-specific oncogenic phenotypes.The Ras-family small GTPase RAB25 can exert both pro- and anti-oncogenic functions. Here, the authors develop all-hydrocarbon stabilized peptides targeting RAB25 and influencing the context-specificity phenotypes in cancer cell lines.

Feng ZH, Fang Y, Zhao LY, et al.
RIN1 promotes renal cell carcinoma malignancy by activating EGFR signaling through Rab25.
Cancer Sci. 2017; 108(8):1620-1627 [PubMed] Free Access to Full Article Related Publications
We previously identified the important role of RIN1 expression in the prognosis of clear cell renal cell carcinoma (ccRCC). The role of RIN1 in ccRCC malignancy and underlying molecular mechanisms remain unclear. Here we report that ccRCC cells and tissues expressed more RIN1 than normal controls. Gain-of-function and loss-of-function studies demonstrated that RIN1 enhanced ccRCC cell growth, migration and invasion abilities in vitro and promoted tumor growth and metastasis in vivo. Mechanistic studies revealed that RIN1 has an activating effect on EGFR signaling in ccRCC. In addition, we unveil Rab25, a critical GTPase in ccRCC malignancy, as a functional RIN1 interacting partner. Knockdown of Rab25 eliminated the augmentation of carcinoma cell proliferation, migration and invasion by ectopic RIN1. We also confirmed that RIN1 and Rab25 expression correlates with the overall-survival of ccRCC patients from TCGA. These findings suggest that RIN1 plays an important oncogenic role in ccRCC malignancy by activation of EGFR signaling through interacting with Rab25, and RIN1 could be employed as an effective therapeutic target for ccRCC.

Ding B, Cui B, Gao M, et al.
Knockdown of Ras-Related Protein 25 (Rab25) Inhibits the In Vitro Cytotoxicity and In Vivo Antitumor Activity of Human Glioblastoma Multiforme Cells.
Oncol Res. 2017; 25(3):331-340 [PubMed] Related Publications
Ras-related protein 25 (Rab25) is a member of the Rab family, and it has been reported to play an important role in tumorigenesis. However, its direct involvement in human glioblastoma multiforme (GBM) is still unclear. The aim of the current study was to investigate the potential role of Rab25 in the growth, proliferation, invasion, and migration of human GBM. Our results showed that Rab25 expression was significantly higher in human GBM cell lines compared with a normal astrocyte cell line. In vitro functional studies revealed that knockdown of Rab25 reduced cell proliferation and inhibited invasion and migration of GBM cells. In vivo experiments showed that knockdown of Rab25 attenuated the tumor growth in nude mice. Finally, knockdown of Rab25 significantly inhibited the phosphorylation levels of PI3K and AKT in GBM cells. Taken together, these findings indicate that Rab25 may act as a tumor promoter in human GBM and that approaches to target Rab25 may provide a novel strategy to treat this disease.

Mitra S, Federico L, Zhao W, et al.
Rab25 acts as an oncogene in luminal B breast cancer and is causally associated with Snail driven EMT.
Oncotarget. 2016; 7(26):40252-40265 [PubMed] Free Access to Full Article Related Publications
The Rab GTPases regulate vesicular trafficking machinery that transports and delivers a diverse pool of cargo, including growth factor receptors, integrins, nutrient receptors and junction proteins to specific intracellular sites. The trafficking machinery is indeed a major posttranslational modifier and is critical for cellular homeostasis. Deregulation of this stringently controlled system leads to a wide spectrum of disorders including cancer. Herein we demonstrate that Rab25, a key GTPase, mostly decorating the apical recycling endosome, is a dichotomous variable in breast cancer cell lines with higher mRNA and protein expression in Estrogen Receptor positive (ER+ve) lines. Rab25 and its effector, Rab Coupling Protein (RCP) are frequently coamplified and coordinately elevated in ER+ve breast cancers. In contrast, Rab25 levels are decreased in basal-like and almost completely lost in claudin-low tumors. This dichotomy exists despite the presence of the 1q amplicon that hosts Rab25 across breast cancer subtypes and is likely due to differential methylation of the Rab25 promoter. Functionally, elevated levels of Rab25 drive major hallmarks of cancer including indefinite growth and metastasis but in case of luminal B breast cancer only. Importantly, in such ER+ve tumors, coexpression of Rab25 and its effector, RCP is significantly associated with a markedly worsened clinical outcome. Importantly, in claudin-low cell lines, exogenous Rab25 markedly inhibits cell migration. Similarly, during Snail-induced epithelial to mesenchymal transition (EMT) exogenous Rab25 potently reverses Snail-driven invasion. Overall, this study substantiates a striking context dependent role of Rab25 in breast cancer where Rab25 is amplified and enhances aggressiveness in luminal B cancers while in claudin-low tumors, Rab25 is lost indicating possible anti-tumor functions.

Clausen MJ, Melchers LJ, Mastik MF, et al.
RAB25 expression is epigenetically downregulated in oral and oropharyngeal squamous cell carcinoma with lymph node metastasis.
Epigenetics. 2016; 11(9):653-663 [PubMed] Free Access to Full Article Related Publications
Oral and oropharyngeal squamous cell carcinoma (OOSCC) have a low survival rate, mainly due to metastasis to the regional lymph nodes. For optimal treatment of these metastases, a neck dissection is required; however, inaccurate detection methods results in under- and over-treatment. New DNA prognostic methylation biomarkers might improve lymph node metastases detection. To identify epigenetically regulated genes associated with lymph node metastases, genome-wide methylation analysis was performed on 6 OOSCC with (pN+) and 6 OOSCC without (pN0) lymph node metastases and combined with a gene expression signature predictive for pN+ status in OOSCC. Selected genes were validated using an independent OOSCC cohort by immunohistochemistry and pyrosequencing, and on data retrieved from The Cancer Genome Atlas. A two-step statistical selection of differentially methylated sequences revealed 14 genes with increased methylation status and mRNA downregulation in pN+ OOSCC. RAB25, a known tumor suppressor gene, was the highest-ranking gene in the discovery set. In the validation sets, both RAB25 mRNA (P = 0.015) and protein levels (P = 0.012) were lower in pN+ OOSCC. RAB25 mRNA levels were negatively correlated with RAB25 methylation levels (P < 0.001) but RAB25 protein expression was not. Our data revealed that promoter methylation is a mechanism resulting in downregulation of RAB25 expression in pN+ OOSCC and decreased expression is associated with lymph node metastasis. Detection of RAB25 methylation might contribute to lymph node metastasis diagnosis and serve as a potential new therapeutic target in OOSCC.

Gomez-Roman N, Sahasrabudhe NM, McGregor F, et al.
Hypoxia-inducible factor 1 alpha is required for the tumourigenic and aggressive phenotype associated with Rab25 expression in ovarian cancer.
Oncotarget. 2016; 7(16):22650-64 [PubMed] Free Access to Full Article Related Publications
The small GTPase Rab25 has been functionally linked to tumour progression and aggressiveness in ovarian cancer and promotes invasion in three-dimensional environments. This type of migration has been shown to require the expression of the hypoxia-inducible factor 1 alpha (HIF-1α). In this report we demonstrate that Rab25 regulates HIF-1α protein expression in an oxygen independent manner in a panel of cancer cell lines. Regulation of HIF-1α protein expression by Rab25 did not require transcriptional upregulation, but was dependent on de novo protein synthesis through the Erbb2/ERK1/2 and p70S6K/mTOR pathways. Rab25 expression induced HIF-1 transcriptional activity, increased cisplatin resistance, and conferred intraperitoneal growth to the A2780 cell line in immunocompromised mice. Targeting HIF1 activity by silencing HIF-1β re-sensitised cells to cisplatin in vitro and reduced tumour formation of A2780-Rab25 expressing cells in vivo in a mouse ovarian peritoneal carcinomatosis model. Similar effects on cisplatin resistance in vitro and intraperitoneal tumourigenesis in vivo were obtained after HIF1b knockdown in the ovarian cancer cell line SKOV3, which expresses endogenous Rab25 and HIF-1α at atmospheric oxygen concentrations. Our results suggest that Rab25 tumourigenic potential and chemoresistance relies on HIF1 activity in aggressive and metastatic ovarian cancer. Targeting HIF-1 activity may potentially be effective either alone or in combination with standard chemotherapy for aggressive metastatic ovarian cancer.

Geng D, Zhao W, Feng Y, Liu J
Overexpression of Rab25 promotes hepatocellular carcinoma cell proliferation and invasion.
Tumour Biol. 2016; 37(6):7713-8 [PubMed] Related Publications
Rab25 was reported to be associated with several human cancers and malignant biological behavior of cancer cells. The goal of the present study was to determine its expression pattern and biological function in human hepatocellular carcinoma (HCC). We examined Rab25 protein in 92 cases of HCC tissues and 3 HCC cell lines. The results showed that Rab25 was upregulated in HCC tissues and cells compared with normal liver tissues and cell line. Rab25 overexpression correlated with advanced tumor stage and nodal metastasis. Rab25 small interfering RNA (siRNA) was employed in Bel7402 and SK-Hep-1 cell lines. Cell Counting Kit-8 (CCK-8) assay and colony formation assay showed that Rab25 depletion blocked cell growth rate and inhibited colony formation ability. Transwell assay showed that Rab25 depletion negatively regulated the invading ability of HCC cells. To explore the possible mechanisms, we checked several signaling pathways and found that Rab25 depletion downregulated AKT phosphorylation. In addition, luciferase reporter assay showed that Rab25 depletion inhibited the Wnt signaling pathway and its target genes such as cyclin D1, c-myc, and MMP7. In conclusion, Rab25 is overexpressed in human HCC and contributes to cancer cell proliferation and invasion possibly through regulation of the Wnt signaling pathway.

Kikuchi M, Yamashita K, Waraya M, et al.
Epigenetic regulation of ZEB1-RAB25/ESRP1 axis plays a critical role in phenylbutyrate treatment-resistant breast cancer.
Oncotarget. 2016; 7(2):1741-53 [PubMed] Free Access to Full Article Related Publications
Phenylbutyrate (PB) is a histone deacetylase antagonist that also exhibits antitumor activity. In this study, we used 7 breast cancer cell lines to identify biomarker candidates that predict PB sensitivity in breast cancer.Comprehensive gene expression profiles were compared using microarrays, and the importance of the identified genes to PB sensitivity was confirmed in gene transfection experiments. CRL and MDAMB453 cells were identified as PB-sensitive, while MDAMB231 cells were PB-resistant.RAB25 and ESRP1 were identified as key regulators of PB sensitivity, while ANKD1, ETS1, PTRF, IFI16 and KIAA1199 acted as PB resistance-related genes. Expression of these genes was dramatically altered by DNA demethylation treatments. RAB25 expression inhibited IFI16 and PTRF, while ESRP1 expression suppressed ANKRD1, ETS1, and KIAA1199. Both RAB25 and ESRP1 were suppressed by ZEB1, which was in turn regulated via epigenetic mechanisms. Thus, PB sensitivity is influenced by epigenetic expression alteration of ZEB1. The genes associated with PB sensitivity are downstream targets of ZEB1. Epigenetic regulation of ZEB1 may prove valuable as a critical biomarker for predicting resistance to breast cancer therapies.

Ma YF, Yang B, Li J, et al.
Expression of Ras-related protein 25 predicts chemotherapy resistance and prognosis in advanced non-small cell lung cancer.
Genet Mol Res. 2015; 14(4):13998-4008 [PubMed] Related Publications
Ras-related protein 25 (Rab25) is involved in many human malignancies. However, its role in chemotherapy response and prognosis in advanced non-small cell lung cancer (NSCLC) remains unknown. Therefore, we investigated the relationship between Rab25 and chemotherapy sensitivity and prognosis in NSCLC. Rab25 expression was assessed using immunohistochemistry in 324 advanced NSCLC patients. Its correlations with clinical features were analyzed. Sensitivity to cisplatin (DDP) was compared between DDP-sensitive A549 and DDP-resistant A549/DDP cells. Furthermore, small interfering RNA (siRNA) targeting Rab25 was used for in vitro experiments. Patients with positive Rab25 expression had a significantly lower chemotherapy response rate (P = 0.004) and poorer overall survival (OS, P = 0.0012) than those with negative Rab25 expression. Multivariate analysis indicated that Rab25 expression was an independent prognostic factor for OS (P = 0.016). Moreover, Rab25 expression was significantly higher in A549/DDP cells than in A549 cells. Knockdown of Rab25 by siRNA suppressed cell migration and invasion. Cisplatin resistance in A549/DDP cells was also partially reversed by Rab25 silencing. Rab25 expression is a potential prognostic index for advanced NSCLC patients and its inhibition may improve chemosensitization in NSCLC treatment.

Li Y, Jia Q, Zhang Q, Wan Y
Rab25 upregulation correlates with the proliferation, migration, and invasion of renal cell carcinoma.
Biochem Biophys Res Commun. 2015; 458(4):745-50 [PubMed] Related Publications
Renal cell carcinoma (RCC) is a common urological cancer with a poor prognosis. A recent cohort study revealed that the median survival of RCC patients was only 1.5 years and that <10% of the patients in the study survived up to 5 years. In tumor development, Rab GTPase are known to play potential roles such as regulation of cell proliferation, migration, invasion, communication, and drug resistance in multiple tumors. However, the correlation between Rabs expression and the occurrence, development, and metastasis of RCC remains unclear. In this study, we analyzed the transcriptional levels of 52 Rab GTPases in RCC patients. Our results showed that high levels of Rab25 expression were significantly correlated with RCC invasion classification (P < 0.01), lymph-node metastasis (P < 0.001), and pathological stage (P < 0.01). Conversely, in 786-O and A-498 cells, knocking down Rab25 protein expression inhibited cell proliferation, migration, and invasion. Our results also demonstrated that Rab25 is a target gene of let-7d, and further suggested that Rab25 upregulation in RCC is due to diminished expression of let-7d. These findings indicate that Rab25 might be a novel candidate molecule involved in RCC development, thus identifying a potential biological therapeutic target for RCC.

Bhat AA, Pope JL, Smith JJ, et al.
Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis.
Oncogene. 2015; 34(35):4570-80 [PubMed] Free Access to Full Article Related Publications
In normal colon, claudin-7 is one of the highly expressed claudin proteins and its knockdown in mice results in altered epithelial cell homeostasis and neonatal death. Notably, dysregulation of the epithelial homeostasis potentiates oncogenic transformation and growth. However, the role of claudin-7 in the regulation of colon tumorigenesis remains poorly understood. Using a large colorectal cancer (CRC) patient database and mouse models of colon cancer, we found claudin-7 expression to be significantly downregulated in cancer samples. Most notably, forced claudin-7 expression in poorly differentiated and highly metastatic SW620 colon cancer cells induced epithelial characteristics and inhibited their growth in soft agar and tumor growth in vivo. By contrast, knockdown of claudin-7 in HT-29 or DLD-1 cells induced epithelial-to-mesenchymal transition (EMT), colony formation, xenograft-tumor growth in athymic mice and invasion. Importantly, a claudin-7 signature gene profile generated by overlapping the DEGs (differentially expressed genes in a high-throughput transcriptome analysis using claudin-7-manipulated cells) with human claudin-7 signature genes identified high-risk CRC patients. Furthermore, Rab25, a colon cancer suppressor and regulator of the polarized cell trafficking constituted one of the highly upregulated DEGs in claudin-7 overexpressing cells. Notably, silencing of Rab25 expression counteracted the effects of claudin-7 expression and not only increased proliferation and cell invasion but also increased the expression of p-Src and mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 that were suppressed upon claudin-7 overexpression. Of interest, CRC cell lines, which exhibited decreased claudin-7 expression, also exhibited promoter DNA hypermethylation, a modification associated with transcriptional silencing. Taken together, our data demonstrate a previously undescribed role of claudin-7 as a colon cancer suppressor and suggest that loss of claudin-7 potentiates EMT to promote colon cancer, in a manner dependent on Rab25.

Chua CE, Tang BL
The role of the small GTPase Rab31 in cancer.
J Cell Mol Med. 2015; 19(1):1-10 [PubMed] Free Access to Full Article Related Publications
Members of the small GTPase family Rab are emerging as potentially important factors in cancer development and progression. A good number of Rabs have been implicated or associated with various human cancers, and much recent excitement has been associated with the roles of the Rab11 subfamily member Rab25 and its effector, the Rab coupling protein (RCP), in tumourigenesis and metastasis. In this review, we focus on a Rab5 subfamily member, Rab31, and its implicated role in cancer. Well recognized as a breast cancer marker with good prognostic value, recent findings have provided some insights as to the mechanism underlying Rab31's influence on oncogenesis. Levels of Oestrogen Receptor α (ERα)- responsive Rab31 could be elevated through stabilization of its transcript by the RNA binding protein HuR, or though activation by the oncoprotein mucin1-C (MUC1-C), which forms a transcriptional complex with ERα. Elevated Rab31 stabilizes MUC1-C levels in an auto-inductive loop that could lead to aberrant signalling and gene expression associated with cancer progression. Rab31 and its guanine nucleotide exchange factor GAPex-5 have, however, also been shown to enhance early endosome-late endosome transport and degradation of the epidermal growth factor receptor (EGFR). The multifaceted action and influences of Rab31 in cancer is discussed in the light of its new interacting partners and pathways.

Davidson B, Holth A, Hellesylt E, et al.
The clinical role of epithelial-mesenchymal transition and stem cell markers in advanced-stage ovarian serous carcinoma effusions.
Hum Pathol. 2015; 46(1):1-8 [PubMed] Related Publications
We recently identified gene signatures that allow classification of ovarian carcinoma into 5 distinct clinically relevant groups. In the present study, we investigated the clinical role of 10 protein products of the discriminating genes, with focus on epithelial-mesenchymal transition and stem cell markers. Expression of E-cadherin, N-cadherin, P-cadherin, Zeb1, HMGA2, Rab25, CD24, NCAM (CD56), Sox11, and vimentin was assessed in 100 advanced-stage (International Federation of Gynecology and Obstetrics stages III-IV) serous ovarian carcinoma effusions using immunohistochemistry. Results were analyzed for association with clinicopathological parameters, including chemotherapy response, and survival. All 10 proteins were frequently expressed in carcinoma cells. HMGA2 expression was related to older age (P = .015). HMGA2 and NCAM expression was related to stage III disease (P = .011 and P = .023, respectively), and NCAM was overexpressed in peritoneal compared with pleural effusions (P = .001). Vimentin and Zeb1 expression was significantly related to poor chemotherapy response at diagnosis (P = .005 and P = .017, respectively). The associations between NCAM and peritoneal localization and of vimentin and poor chemoresponse were retained after Bonferroni correction. NCAM expression was associated with a trend for shorter overall survival in univariate survival analysis (P = .187), but emerged as an independent prognosticator in Cox multivariate analysis (P = .042). This study identifies vimentin and Zeb1 as markers of poor chemoresponse in metastatic serous ovarian carcinoma effusions and suggests NCAM as potential prognostic marker in metastatic disease. The generally limited prognostic role of the studied markers emphasizes the difficulty in applying data obtained in studies of primary ovarian carcinomas to analyses of ovarian carcinoma effusions, reflecting the unique biology of the latter.

Fan Y, Wang L, Han X, et al.
Rab25 is responsible for phosphoinositide 3-kinase/AKT‑mediated cisplatin resistance in human epithelial ovarian cancer cells.
Mol Med Rep. 2015; 11(3):2173-8 [PubMed] Related Publications
Rab25, a member of the Rab family of small guanosine triphosphatase, was reported to have an essential role in the development of human epithelial ovarian cancer. The present study demonstrated that Rab25 mediated the sensitivity of ovarian cancer to cisplatin, a first‑line chemotherapeutic agent for the treatment of ovarian cancer in the clinic. Overexpression of Rab25 and increased phosphoinositide 3‑kinase (PI3K)/AKT signaling were detected in cisplatin‑resistant SKOV‑3 cells compared with those in cisplatin‑sensitive ES‑2 cells. The results of the present study indicated that cisplatin resistance was primarily due to reduced G1 cell cycle arrest following cisplatin treatment in SKOV‑3 cells. By contrast, the corresponding phenomenon was not observed following treatment with a Rab25‑specific small interfering RNA or treatment with the PI3K/AKT inhibitor LY294002. Of note, inhibition of the PI3K/AKT pathway reduced Rab25 gene expression and sensitized SKOV‑3 cells to cisplatin. Furthermore, knockdown of Rab25 showed an effect comparable with blocking the PI3K/AKT pathway. In conclusion, the results of the present study demonstrated that PI3K/AKT and Rab25 significantly contributed to cisplatin resistance in human epithelial ovarian cancer; in addition, silencing Rab25 or inhibiting the PI3K/AKT pathway markedly increased the sensitivity of these cells to cisplatin.

Nikoshkov A, Broliden K, Attarha S, et al.
Expression pattern of the PRDX2, RAB1A, RAB1B, RAB5A and RAB25 genes in normal and cancer cervical tissues.
Int J Oncol. 2015; 46(1):107-12 [PubMed] Related Publications
Cervical cancer is the second most prevalent malignancy among women worldwide, and additional objective diagnostic markers for this disease are needed. Given the link between cancer development and alternative splicing, we aimed to analyze the splicing patterns of the PRDX2, RAB1A, RAB1B, RAB5A and RAB25 genes, which are associated with different cancers, in normal cervical tissue, preinvasive cervical lesions and invasive cervical tumors, to identify new objective diagnostic markers. Biopsies of normal cervical tissue, preinvasive cervical lesions and invasive cervical tumors, were subjected to rapid amplification of cDNA 3' ends (3' RACE) RT‑PCR. Resulting PCR products were analyzed on agarose gels, gel‑purified and sequenced. Normal cervical tissue, preinvasive cervical lesions and invasive cervical tumors contained one PCR product corresponding to full‑length PRDX2, RAB5A and RAB25 transcripts. All tissues contained two RAB1A‑specific PCR products corresponding to the full‑length transcript and one new alternatively spliced RAB1A transcript. Invasive cervical tumors contained one PCR product corresponding to the full‑length RAB1B transcript, while all normal cervical tissue and preinvasive cervical lesions contained both the full‑length RAB1B transcript and three new alternatively spliced RAB1B transcripts. Alternative splicing of the RAB1A transcript occurs in all cervical tissues, while alternative splicing of the RAB1B transcript occurs in normal cervical tissue and in preinvasive cervical lesions; not in invasive cervical tumors.

Chen WY, Wu F, You ZY, et al.
Analyzing the differentially expressed genes and pathway cross-talk in aggressive breast cancer.
J Obstet Gynaecol Res. 2015; 41(1):132-40 [PubMed] Related Publications
AIM: The aim of this study was to explore the genes and pathways involved in the aggressive breast cancer cells.
METHODS: The gene expression profiles of GSE40057, including four aggressive breast cell lines and six less aggressive cell lines, were downloaded from the Gene Expression Omnibus (GEO) database. The gene differential expression analysis was carried out with limma software with the method of Bayes for multiple tests. The gene ontology (GO) term enrichment and pathway cross-talk analysis were performed with the online tool of DAVID and Cytoscape software.
RESULTS: A total of 401 differentially expressed genes (DEG), such as pentraxin 3 (PTX3), snail family zinc finger 2 (SNAI2), interleukin-8/6 (IL-8/6), osteonectin (SPARC), matrix metallopeptidase-1 (MMP-1) and Ras-related protein Rab-25 (Rab 25), were identified between aggressive and less aggressive cell lines. They were mainly enriched in the GO terms of response to wounding, negative regulation of cell proliferation and calcium binding. Pathways in cancer dysfunctionally interacted with glyoxylate and dicarboxylate metabolism (P < 0.0001), basal transcription factors (P < 0.0001), tyrosine metabolism (P < 0.0001), calcium signaling pathway (P = 0.0021), FcγR-mediated phagocytosis (P = 0.0022), metabolism of xenobiotics by cytochrome P450 (P = 0.0097) and phagosome (P = 0.0102).
CONCLUSION: The screened aggressive cancer-associated DEG (PTX3, SNAI2, IL-8/6, SPARC, MMP-1 and Rab25) and significant pathways (calcium signaling pathway, tyrosine metabolism, alanine, aspartate and glutamate metabolism) give us new insights into the mechanism of aggressive breast cancer cells, and these DEG may become promising target genes in the treatment of metastatic breast cancer.

Jo U, Park KH, Whang YM, et al.
EGFR endocytosis is a novel therapeutic target in lung cancer with wild-type EGFR.
Oncotarget. 2014; 5(5):1265-78 [PubMed] Free Access to Full Article Related Publications
Oncogenic alterations of epidermal growth factor receptor (EGFR) signaling are frequently observed in lung cancer patients with worse differentiation and poor prognosis. However, the therapeutic efficacy of EGFR-tyrosine kinase inhibitors (TKIs) is currently limited in selected patients with EGFR mutations. Therefore, in this study, we investigated the potential molecular mechanism that contributes to cell viability and the response of gefitinib, one of the EGFR-TKIs, in lung cancer models with wide-type EGFR (wtEGFR). Interestingly, we found that EGF-induced EGFR endocytosis is existed differently between gefitinib-sensitive and -insensitive lung cancer cell lines. Suppressing EGFR endocytos decreased cell viability and increased apoptotic cell death in gefitinib-insensitive lung cancer with wtEGFR in vitro and in vivo. In addition, we found that Rab25 was differentially expressed in between gefitinib-sensitive and -insensitive lung cancer cells. Rab25 knockdown caused the changed EGFR endocytosis and reverted the gefitinib response in gefitinib-sensitive lung cancer with wtEGFR in vitro and in vivo. Taken together, our findings suggest a novel insight that EGFR endocytosis is a rational therapeutic target in lung cancer with wtEGFR, in which the combined efficacy with gefitinib is expected. Furthermore, we demonstrated that Rab25 plays an important role in EGFR endocytosis and gefitinib therapy.

Zhang J, Wei J, Lu J, et al.
Overexpression of Rab25 contributes to metastasis of bladder cancer through induction of epithelial-mesenchymal transition and activation of Akt/GSK-3β/Snail signaling.
Carcinogenesis. 2013; 34(10):2401-8 [PubMed] Related Publications
Rab25, an epithelial-specific member of the Rab family of small guanosine triphosphatases, is associated with several human cancers. The goal of this study was to determine its function in bladder cancer (BC). We examined the Rab25 expression pattern in two different cohorts of BC patients treated with radical cystectomy by quantitative PCR, western blotting and immunohistochemical staining. A series of in vitro and in vivo assays were performed to elucidate the function of Rab25 in BC and its underlying mechanisms. Rab25 expression was significantly elevated at both the messenger RNA and protein levels in BCs compared with normal bladder tissues. High Rab25 expression was closely associated with lymph node (LN) metastasis and was an independent predictor for poor disease-free survival in BC patients. Downregulation of Rab25 in BC cells markedly inhibited invasive motility in vitro and metastatic potential in vivo. In addition, downregulation of Rab25 in BC EJ and T24 cells increased the expression levels of epithelial markers (E-cadherin and α-catenin) and decreased the levels of mechamechy markers (vimentin and fibronectin). Simultaneously, downregulation of Rab25 in EJ and T24 cells resulted in the inactivation of downstream phosphorylated protein kinase B (p-Akt), phosphorylated glycogen synthase kinase-β (p-GSK-3β) and snail signaling. This study demonstrates that Rab25 can promote BC metastasis through induction of epithelial-mesenchymal transition process and activation of Akt/GSK-3β/Snail signaling pathway; Rab25 expression level can predict LN metastasis and inferior clinical outcome in BC patients.

Pénzváltó Z, Tegze B, Szász AM, et al.
Identifying resistance mechanisms against five tyrosine kinase inhibitors targeting the ERBB/RAS pathway in 45 cancer cell lines.
PLoS One. 2013; 8(3):e59503 [PubMed] Free Access to Full Article Related Publications
Because of the low overall response rates of 10-47% to targeted cancer therapeutics, there is an increasing need for predictive biomarkers. We aimed to identify genes predicting response to five already approved tyrosine kinase inhibitors. We tested 45 cancer cell lines for sensitivity to sunitinib, erlotinib, lapatinib, sorafenib and gefitinib at the clinically administered doses. A resistance matrix was determined, and gene expression profiles of the subsets of resistant vs. sensitive cell lines were compared. Triplicate gene expression signatures were obtained from the caArray project. Significance analysis of microarrays and rank products were applied for feature selection. Ninety-five genes were also measured by RT-PCR. In case of four sunitinib resistance associated genes, the results were validated in clinical samples by immunohistochemistry. A list of 63 top genes associated with resistance against the five tyrosine kinase inhibitors was identified. Quantitative RT-PCR analysis confirmed 45 of 63 genes identified by microarray analysis. Only two genes (ANXA3 and RAB25) were related to sensitivity against more than three inhibitors. The immunohistochemical analysis of sunitinib-treated metastatic renal cell carcinomas confirmed the correlation between RAB17, LGALS8, and EPCAM and overall survival. In summary, we determined predictive biomarkers for five tyrosine kinase inhibitors, and validated sunitinib resistance biomarkers by immunohistochemistry in an independent patient cohort.

Krishnan M, Lapierre LA, Knowles BC, Goldenring JR
Rab25 regulates integrin expression in polarized colonic epithelial cells.
Mol Biol Cell. 2013; 24(6):818-31 [PubMed] Free Access to Full Article Related Publications
Rab25 is a tumor suppressor for colon cancer in humans and mice. To identify elements of intestinal polarity regulated by Rab25, we developed Caco2-BBE cell lines stably expressing short hairpin RNA for Rab25 and lines rescuing Rab25 knockdown with reexpression of rabbit Rab25. Rab25 knockdown decreased α2-, α5-, and β1-integrin expression. We observed colocalization and direct association of Rab25 with α5β1-integrins. Rab25 knockdown also up-regulated claudin-1 expression, increased transepithelial resistance, and increased invasive behavior. Rab25-knockdown cells showed disorganized brush border microvilli with decreases in villin expression. All of these changes were reversed by reintroduction of rabbit Rab25. Rab25 knockdown altered the expression of 29 gene transcripts, including the loss of α5-integrin transcripts. Rab25 loss decreased expression of one transcription factor, ETV4, and overexpression of ETV4 in Rab25-knockdown cells reversed losses of α5β1-integrin. The results suggest that Rab25 controls intestinal cell polarity through the regulation of gene expression.

Amornphimoltham P, Rechache K, Thompson J, et al.
Rab25 regulates invasion and metastasis in head and neck cancer.
Clin Cancer Res. 2013; 19(6):1375-88 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is one of the 10 most common cancers with a 50% five-year survival rate, which has remained unchanged for the past three decades. One of the major reasons for the aggressiveness of this cancer is that HNSCCs readily metastasize to cervical lymph nodes that are abundant in the head and neck region. Hence, discovering new molecules controlling the metastatic process as well as understanding their regulation at the molecular level are essential for effective therapeutic strategies.
EXPERIMENTAL DESIGN: Rab25 expression level was analyzed in HNSCC tissue microarray. We used a combination of intravital microscopy in live animals and immunofluorescence in an in vitro invasion assay to study the role of Rab25 in tumor cell migration and invasion.
RESULTS: In this study, we identified the small GTPase Rab25 as a key regulator of HNSCC metastasis. We observed that Rab25 is downregulated in HNSCC patients. Next, we determined that reexpression of Rab25 in a metastatic cell line is sufficient to block invasion in a three-dimensional collagen matrix and metastasis to cervical lymph nodes in a mouse model for oral cancer. Specifically, Rab25 affects the organization of F-actin at the cell surface, rather than cell proliferation, apoptosis, or tumor angiogenesis.
CONCLUSION: These findings suggest that Rab25 plays an important role in tumor migration and metastasis, and that understanding its function may lead to the development of new strategies to prevent metastasis in oral cancer patients.

Mitra S, Cheng KW, Mills GB
Rab25 in cancer: a brief update.
Biochem Soc Trans. 2012; 40(6):1404-8 [PubMed] Free Access to Full Article Related Publications
Derailed endocytosis is a hallmark of cancer. The endocytic pathway, as demonstrated by our laboratory, is a frequent target of genomic aberrations in cancer and plays a critical role in the maintenance of cellular polarity, stem cell function, bioenergetics, proliferation, motility, invasion, metastasis, apoptosis and autophagy. The Rab GTPases, along with their effectors, are critical regulators of this endocytic machinery and can have a huge impact on the cellular itinerary of growth and metabolism. Rab25 is an epithelial-cell-specific member of the Rab GTPase superfamily, sharing close homology with Rab11a, the endosomal recycling Rab GTPase. RAB25 has been implicated in various cancers, with reports presenting it as both an oncogene and a tumour-suppressor gene. At the cellular level, Rab25 was shown to contribute to invasiveness of cancer cells by regulating integrin trafficking. Recently, our laboratory uncovered a critical role for Rab25 in cellular energetics. Assimilating all of the existing evidence, in the present review, we give an updated overview of the complex and often context-dependent role of Rab25 in cancer.

Tringali C, Lupo B, Silvestri I, et al.
The plasma membrane sialidase NEU3 regulates the malignancy of renal carcinoma cells by controlling β1 integrin internalization and recycling.
J Biol Chem. 2012; 287(51):42835-45 [PubMed] Free Access to Full Article Related Publications
The human plasma membrane sialidase NEU3 is a key enzyme in the catabolism of membrane gangliosides, is crucial in the regulation of cell surface processes, and has been demonstrated to be significantly up-regulated in renal cell carcinomas (RCCs). In this report, we show that NEU3 regulates β1 integrin trafficking in RCC cells by controlling β1 integrin recycling to the plasma membrane and controlling activation of the epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK)/protein kinase B (AKT) signaling. NEU3 silencing in RCC cells increased the membrane ganglioside content, in particular the GD1a content, and changed the expression of key regulators of the integrin recycling pathway. In addition, NEU3 silencing up-regulated the Ras-related protein RAB25, which directs internalized integrins to lysosomes, and down-regulated the chloride intracellular channel protein 3 (CLIC3), which induces the recycling of internalized integrins to the plasma membrane. In this manner, NEU3 silencing enhanced the caveolar endocytosis of β1 integrin, blocked its recycling and reduced its levels at the plasma membrane, and, consequently, inhibited EGFR and FAK/AKT. These events had the following effects on the behavior of RCC cells: they (a) decreased drug resistance mediated by the block of autophagy and the induction of apoptosis; (b) decreased metastatic potential mediated by down-regulation of the metalloproteinases MMP1 and MMP7; and (c) decreased adhesion to collagen and fibronectin. Therefore, our data identify NEU3 as a key regulator of the β1 integrin-recycling pathway and FAK/AKT signaling and demonstrate its crucial role in RCC malignancy.

Gonzalez-Angulo AM, Liu S, Chen H, et al.
Functional proteomics characterization of residual breast cancer after neoadjuvant systemic chemotherapy.
Ann Oncol. 2013; 24(4):909-16 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The purpose of this study was to determine the functional proteomic characteristics of residual breast cancer and hormone receptor (HR)-positive breast cancer after neoadjuvant systemic chemotherapy, and their relationship with patient outcomes.
METHODS: Reverse phase protein arrays of 76 proteins were carried out. A boosting approach in conjunction with a Cox proportional hazard model defined relapse predictors. A risk score (RS) was calculated with the sum of the coefficients from the final model. Survival outcomes and associations of the RS with relapse were estimated. An independent test set was used to validate the results.
RESULTS: Test (n = 99) and validation sets (n = 79) were comparable. CoxBoost revealed a three-biomarker (CHK1pS345, Caveolin1, and RAB25) and a two-biomarker (CD31 and Cyclin E1) model that correlated with recurrence-free survival (RFS) in all residual breast cancers and in HR-positive disease, respectively. Unsupervised clustering split patients into high- and low risk of relapse groups with different 3-year RFS (P ≤ 0.001 both). RS was a substantial predictor of RFS (P = 0.0008 and 0.0083) after adjustment for other substantial characteristics. Similar results were found in validation sets.
CONCLUSIONS: We found models that independently predicted RFS in all residual breast cancer and in residual HR-positive disease that may represent potential targets of therapy in this resistant disease.

Tong M, Chan KW, Bao JY, et al.
Rab25 is a tumor suppressor gene with antiangiogenic and anti-invasive activities in esophageal squamous cell carcinoma.
Cancer Res. 2012; 72(22):6024-35 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is a devastating disease characterized by distinctly high incidences and mortality rates. However, there remains limited understanding of molecular events leading to development and progression of the disease, which are of paramount importance to defining biomarkers for diagnosis, prognosis, and personalized treatment. By high-throughout transcriptome sequence profiling of nontumor and ESCC clinical samples, we identified a subset of significantly differentially expressed genes involved in integrin signaling. The Rab25 gene implicated in endocytic recycling of integrins was the only gene in this group significantly downregulated, and its downregulation was confirmed as a frequent event in a second larger cohort of ESCC tumor specimens by quantitative real-time PCR and immunohistochemical analyses. Reduced expression of Rab25 correlated with decreased overall survival and was also documented in ESCC cell lines compared with pooled normal tissues. Demethylation treatment and bisulfite genomic sequencing analyses revealed that downregulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation. Functional studies using lentiviral-based overexpression and suppression systems lent direct support of Rab25 to function as an important tumor suppressor with both anti-invasive and -angiogenic abilities, through a deregulated FAK-Raf-MEK1/2-ERK signaling pathway. Further characterization of Rab25 may provide a prognostic biomarker for ESCC outcome prediction and a novel therapeutic target in ESCC treatment.

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