H-RAS, K-RAS, and N-RAS Gene Activation in Human Bladder Cancers

Przybojewska, Barbara; Jagiełło, Alicja; Jalmuzna, P

doi:10.1016/s0165-4608(00)00223-5

Cited by 54 publications

(34 citation statements)

References 8 publications

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“…The KRAS gene, located in 12p12.1, encodes a protein that is a member of the small gTPase superfamily (48). Recently, an abnormal KRAS expression has been reported to be involved in human cancers, such as gastric (27), pancreatic (28), bladder (29), lung (49) and breast cancer (50). In adittion, aberrantly expressed and somatic activating mutations in KRAS are involved in tumourigenesis and tumour development, including pilocytic astrocytoma (51), nasopharyngeal carcinoma (52), colorectal (53) and lung cancer (54).…”

Section: Discussionmentioning

confidence: 99%

“…Of these target candidate genes, KRAS (Fig. 3A) attracted our attention immediately since it has been implicated in tumourigenesis and progression (27)(28)(29). To confirm this hypothesis, luciferase reporter assays were performed in SK-MEL-28 and A375 cells transfected with miR-326 mimics or miR-NC along with pmirgLO-KRAS-3'-UTR Wt or pmirgLO-KRAS-3'-UTR Mut.…”

Section: Kras Is a Direct Target Gene Of Mir-326 In Melanomamentioning

confidence: 99%

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MicroRNA-326 inhibits melanoma progression by targeting KRAS and suppressing the AKT and ERK signalling pathways

Kang

Zhang

et al. 2017

Oncol Rep

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Abstract. Melanoma is the seventh most common malignancy in females and the fifth most common cancer in males worldwide. An increasing number of studies have reported that microRNA (miRNA) dysregulation is frequently observed in various types of human cancers, including melanoma. Abnormally expressed miRNAs play an important role in melanoma formation and progression by serving as potential biomarkers and therapeutic targets. Recently, miRNA-326 (miR-326) has been reported to be differentially expressed in various types of tissues and play important roles in tumourigenesis and tumour development. However, the expression levels, biological roles and underlying mechanisms of miR-326 in melanoma remain unknown. In the present study, we demonstrated that miR-326 was significantly downregulated in melanoma tissues and cell lines. Functional assays revealed that the enforced expression of miR-326 suppressed melanoma cell proliferation and invasion and increased cell apoptosis in vitro. Using bioinformatic analysis, Kirsten rat sarcoma viral oncogene homolog (KRAS) was predicted as a potential target of miR-326. Luciferase reporter assay confirmed that miR-326 could directly target the 3'-untranslated region of KRAS. In addition, reverse transcription-quantitative polymerase chain reaction and western blot analysis revealed that miR-326 upregulation decreased the KRAS expression in melanoma cells at both the mRNA and protein level. Furthermore, KRAS was upregulated in melanoma tissues and inversely correlated with miR-326 expression. In addition, the KRAS knockdown phenocopied the tumour-suppressing effects of miR-326 overexpression on melanoma cells. The restoration of the expression of KRAS markedly reversed the antitumour effects induced by miR-326 overexpression in melanoma cells. Further experiments indicated that miR-326 inactivated the AKT and ERK signalling pathways in melanoma. Collectively, these results revealed that miR-326 serves as a tumour suppressor in melanoma by targeting KRAS and regulating the AKT and ERK signalling pathways, indicating that miR-326 may be a promising therapeutic target for melanoma patients.

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Section: Discussionmentioning

confidence: 99%

Section: Kras Is a Direct Target Gene Of Mir-326 In Melanomamentioning

confidence: 99%

MicroRNA-326 inhibits melanoma progression by targeting KRAS and suppressing the AKT and ERK signalling pathways

Kang

Zhang

et al. 2017

Oncol Rep

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“…Few studies have screened NRAS and KRAS2, but mutations have been described previously in KRAS2 (Uchida et al, 1995;Olderoy et al, 1998;Ayan et al, 2001). A single study that examined NRAS using restriction fragment polymorphism analysis reported a high frequency of mutation, but these were not confirmed by sequencing (Przybojewska et al, 2000). To date a comprehensive analysis of all three Ras genes has not been carried out in a large series of bladder tumours.…”

Section: Introductionmentioning

confidence: 99%

FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma

et al. 2005

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Fibroblast growth factor receptor 3 (FGFR3) mutations are frequent in superficial urothelial cell carcinoma (UCC). Ras gene mutations are also found in UCC. As oncogenic activation of both FGFR3 and Ras is predicted to result in stimulation of the mitogen-activated protein kinase (MAPK) pathway, we hypothesized that these might be mutually exclusive events. HRAS mutation has been widely studied in UCC, but all three Ras gene family members have not been screened for mutation in the same sample series. We screened 98 bladder tumours and 31 bladder cell lines for mutations in FGFR3, HRAS, NRAS and KRAS2. FGFR3 mutations were present in 54 tumours (55%) and three cell lines (10%), and Ras gene mutations in 13 tumours (13%) and four cell lines (13%). These included mutations in all three Ras genes; ten in HRAS, four in KRAS2 and four in NRAS and these were not associated with either tumour grade or stage. In no cases were Ras and FGFR3 mutation found together. This mutual exclusion suggests that FGFR3 and Ras gene mutation may represent alternative means to confer the same phenotype on UCC cells. If these events have biological equivalence, Ras mutant invasive UCC may represent a novel subgroup.

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“…Since then, it has become one of the most frequently identified oncogenes in human tumors, but ironically, its precise role in urothelial tumorigenesis has continued to be controversial. Although Ha-ras (as opposed to Ki-ras and N-ras) remains the main target of mutational activation in bladder tumors, the mutation frequency in different patient cohorts ranges from 0% to 84%, with no satisfactory explanation for such a wide variation (9)(10)(11)(12). Some studies have shown an association of the Ha-ras mutations with low-grade, noninvasive superficial papillary urothelial tumors (10), while others have suggested that the mutations play a role in bladder tumor invasion (13,14); and still others found no correlation between Ha-ras mutations and tumor progression (15).…”

Section: Introductionmentioning

confidence: 99%

Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis

Mo¹,

Zheng²,

Huang³

et al. 2007

J. Clin. Invest.

104

118

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Although ras is a potent mitogenic oncogene, its tumorigenicity depends on cellular context and cooperative events. Here we show that low-level expression of a constitutively active Ha-ras in mouse urothelium induces simple urothelial hyperplasia that is resistant to progression to full-fledged bladder tumors even in the absence of Ink4a/Arf. In stark contrast, doubling of the gene dosage of the activated Ha-ras triggered earlyonset, rapidly growing, and 100% penetrant tumors throughout the urinary tract. Tumor initiation required superseding a rate-limiting step between simple and nodular hyperplasia, the latter of which is marked by the emergence of mesenchymal components and the coactivation of AKT and STAT pathways as well as PTEN inactivation. These results indicate that overactivation of Ha-ras is both necessary and sufficient to induce bladder tumors along a low-grade, noninvasive papillary pathway, and they shed light on the recent findings that ras activation, via point mutation, overexpression, or intensified signaling from FGF receptor 3, occurs in 70%-90% of these tumors in humans. Our results highlight the critical importance of the dosage/strength of Ha-ras activation in dictating its tumorigenicity -a mechanism of oncogene activation not fully appreciated to date. Finally, our results have clinical implications, as inhibiting ras and/or its downstream effectors, such as AKT and STAT3/5, could provide alternative means to treat low-grade, superficial papillary bladder tumors, the most common tumor in the urinary system.

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H-RAS, K-RAS, and N-RAS Gene Activation in Human Bladder Cancers

Cited by 54 publications

References 8 publications

MicroRNA-326 inhibits melanoma progression by targeting KRAS and suppressing the AKT and ERK signalling pathways

MicroRNA-326 inhibits melanoma progression by targeting KRAS and suppressing the AKT and ERK signalling pathways

FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma

Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis

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