Overexpression of Ran GTPase Components Regulating Nuclear Export, but not Mitotic Spindle Assembly, Marks Chromosome Instability and Poor Prognosis in Breast Cancer

Vaidyanathan, Srividya; Thangavelu, Pulari U.; Duijf, Pascal H.G.

doi:10.1007/s11523-016-0432-y

Cited by 37 publications

(48 citation statements)

References 60 publications

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“…In an effort to independently validate these results, we used a combination of 28 other microarray datasets, as described [19, 20]. However, this showed that COL4A1 expression did not significantly change (1.15-fold increase, p = 0.2574, t test, n = 1137) and that COL4A2 expression was significantly reduced (1.53-fold decrease, p = 7.97 × 10 −10 , n = 2830), rather than increased (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…and the Nottingham Prognostic Index, were performed as described [17, 18]. Survival analyses were performed using a single clinical feature at a time, i.e., distant metastasis-free survival, recurrence-free survival, or overall survival, and by splitting the gene expression in tumors into below (low) and above (high) the median expression level, as described [19, 39]. Statistical analyses were performed using log-rank Mantel-Cox tests.…”

Section: Methodsmentioning

confidence: 99%

“…Validation analyses for COL4A1 , COL4A2 , and COL17A1 gene expression in breast cancer were performed using 28 datasets, as previously described [19, 20]. In addition, the TCGA (The Cancer Genome Atlas) breast cancer and cervical cancer Illumina HiSeq RNA Seq V2 (RSEM-analyzed) datasets [21, 22] were used to compare COL17A1 expression levels in matched normal control to breast and cervical cancer samples.…”

Section: Methodsmentioning

confidence: 99%

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In epithelial cancers, aberrant COL17A1 promoter methylation predicts its misexpression and increased invasion

et al. 2016

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BackgroundMetastasis is a leading cause of death among cancer patients. In the tumor microenvironment, altered levels of extracellular matrix proteins, such as collagens, can facilitate the first steps of cancer cell metastasis, including invasion into surrounding tissue and intravasation into the blood stream. However, the degree of misexpression of collagen genes in tumors remains understudied, even though this knowledge could greatly facilitate the development of cancer treatment options aimed at preventing metastasis.MethodsWe systematically evaluate the expression of all 44 collagen genes in breast cancer and assess whether their misexpression provides clinical prognostic significance. We use immunohistochemistry on 150 ductal breast cancers and 361 cervical cancers and study DNA methylation in various epithelial cancers.ResultsIn breast cancer, various tests show that COL4A1 and COL4A2 overexpression and COL17A1 (BP180, BPAG2) underexpression provide independent prognostic strength (HR = 1.25, 95% CI = 1.17–1.34, p = 3.03 × 10−10; HR = 1.18, 95% CI = 1.11–1.25, p = 8.11 × 10−10; HR = 0.86, 95% CI = 0.81–0.92, p = 4.57 × 10−6; respectively). Immunohistochemistry on ductal breast cancers confirmed that the COL17A1 protein product, collagen XVII, is underexpressed. This strongly correlates with advanced stage, increased invasion, and postmenopausal status. In contrast, immunohistochemistry on cervical tumors showed that collagen XVII is overexpressed in cervical cancer and this is associated with increased local dissemination. Interestingly, consistent with the opposed direction of misexpression in these cancers, the COL17A1 promoter is hypermethylated in breast cancer and hypomethylated in cervical cancer. We also find that the COL17A1 promoter is hypomethylated in head and neck squamous cell carcinoma, lung squamous cell carcinoma, and lung adenocarcinoma, in all of which collagen XVII overexpression has previously been shown.ConclusionsParadoxically, collagen XVII is underexpressed in breast cancer and overexpressed in cervical and other epithelial cancers. However, the COL17A1 promoter methylation status accurately predicts both the direction of misexpression and the increased invasive nature for five out of five epithelial cancers. This implies that aberrant epigenetic control is a key driver of COL17A1 gene misexpression and tumor cell invasion. These findings have significant clinical implications, suggesting that the COL17A1 promoter methylation status can be used to predict patient outcome. Moreover, epigenetic targeting of COL17A1 could represent a novel strategy to prevent metastasis in patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0290-6) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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In epithelial cancers, aberrant COL17A1 promoter methylation predicts its misexpression and increased invasion

et al. 2016

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“…Although no comprehensive studies have been performed in CRC, limited evidence in previous studies has observed overexpression of XPO5 in urothelial (10) and breast cancer (11, 12). Another recent study showed that XPO5 is a critical regulator of cell cycle (13).…”

Section: Introductionmentioning

confidence: 99%

Exportin-5 Functions as an Oncogene and a Potential Therapeutic Target in Colorectal Cancer

Shigeyasu

Okugawa

Toden

et al. 2017

Clinical Cancer Research

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Objective Dysregulated expression of microRNAs (miRNAs) has emerged as a hallmark feature in human cancers. Exportin-5 (XPO5), a karyopherin family member, is a key protein responsible for transporting precursor miRNAs from the nucleus to the cytoplasm. While XPO5 is one of the key regulators of miRNA biogenesis, its functional role and potential clinical significance in colorectal cancer (CRC) remains unclear. Design The expression levels of XPO5 were initially assessed in three genomic datasets, followed by determination and validation of the relationship between XPO5 expression and clinicopathological features in two independent CRC patient cohorts. A functional characterization of XPO5 in CRC was examined by targeted gene silencing in colorectal cancer cell lines and a xenograft animal model. Results XPO5 is upregulated, both at mRNA and protein levels, in CRCs compared with normal tissues. High-XPO5 expression associated with worse clinicopathological features and poor survival in CRC patient cohorts. The siRNA knockdown of XPO5 resulted in reduced cellular proliferation, attenuated invasion, induction of G1/S cell-cycle arrest, and downregulation of key oncogenic miRNAs in CRC cells. These findings were confirmed in a xenograft animal model wherein silencing of XPO5 resulted in the attenuation of tumor growth. Conclusion XPO5 acts like an oncogene in CRC by regulating the expression of miRNAs and may be a potential therapeutic target in CRC.

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“…Elevated expression of XPOT is associated with cell proliferation in human promyelocytic leukemia . Overexpression of XPOT leads to more aggressive and chromosomally unstable breast cancers . However, the role of XPOT in HCC has not been studied before.…”

Section: Discussionmentioning

confidence: 99%

Exportin‐T promotes tumor proliferation and invasion in hepatocellular carcinoma

Jin

Hou

Huang

et al. 2018

Molecular Carcinogenesis

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Exportin‐T (XPOT) belongs to the RAN‐GTPase exportin family that mediates export of tRNA from the nucleus to the cytoplasm. Up‐regulation of XPOT indicates poor prognosis in breast cancer patients. However, the correlation between XPOT and hepatocellular carcinoma (HCC) remains unclear. Here, we found that high expression of XPOT in HCC indicated worse prognosis via bioinformatics analysis. Consistently, immunohistochemical staining of 95 pairs of tumors and adjacent normal liver tissues (ANLT) also showed up‐regulation of XPOT. Small interfering (si) RNA transfection was used to down‐regulate XPOT in HepG2 and 7721 cell lines. Cell Counting Kit‐8 (CCK8) assays were performed to analyze cell proliferation. Cell migration and invasion were measured by scratch wound healing assays and migration assays. Subcutaneous xenograft models were using to explore the role of XPOT in tumor formation in vivo. Down‐regulation of XPOT significantly inhibited tumor proliferation and invasion in vitro and vivo. Gene set enrichment analysis (GSEA) results indicated that XPOT may affect tumor progression through cell cycle and ubiquitin‐mediated proteolysis. Furthermore, knockdown of XPOT caused a block in G0/G1 phase as evidenced by down‐regulation of cyclin‐dependent kinase 1 (CDK1), cyclin‐dependent kinase 2 (CDK2), cyclin‐dependent kinase 4 (CDK4), CyclinA1 (CCNA1), CyclinB1 (CCNB1), CyclinB2 (CCNB2), and CyclinE2 (CCNE2) in HCC cells. In conclusion, our findings indicate that XPOT could serve as a novel biomarker for prognoses and a potential therapeutic target for patients with HCC.

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Overexpression of Ran GTPase Components Regulating Nuclear Export, but not Mitotic Spindle Assembly, Marks Chromosome Instability and Poor Prognosis in Breast Cancer

Cited by 37 publications

References 60 publications

In epithelial cancers, aberrant COL17A1 promoter methylation predicts its misexpression and increased invasion

In epithelial cancers, aberrant COL17A1 promoter methylation predicts its misexpression and increased invasion

Exportin-5 Functions as an Oncogene and a Potential Therapeutic Target in Colorectal Cancer

Exportin‐T promotes tumor proliferation and invasion in hepatocellular carcinoma

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