Increased Rac1 activity and Pak1 overexpression are associated with lymphovascular invasion and lymph node metastasis of upper urinary tract cancer

Kamai, Takao; Shirataki, Hiromichi; Nakanishi, Kenji; Furuya, Nobutaka; Kambara, Tsunehito; Abe, Hideyuki; Oyama, Tetsunari; Yoshida, Keisuke

doi:10.1186/1471-2407-10-164

Cited by 71 publications

(65 citation statements)

References 27 publications

(51 reference statements)

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“…A robust line of studies have provided evidence supporting the crucial role of Rac1 in human cancers. Rac1 expression was associ- ated with invasion and metastasis in urothelial carcinoma (19). Rac1 promoted colon cancer progression through promotion of cell proliferation, survival and migration (36).…”

Section: Discussionmentioning

confidence: 99%

“…Rac1 regulates a diverse spectrum of cellular functions including tumorigenesis (11), angiogenesis (12,13) and metastasis (11,14,15). Overexpression of Rac1 occurs in several different types of tumors including breast (16,17), colon (18), bladder (19), and gastric cancer (20,21). Rac1 overexpression was observed in metastatic gastric (21), breast (15), prostate (22), bladder upper urinary tract cancer (19).…”

Section: Introductionmentioning

confidence: 99%

“…Overexpression of Rac1 occurs in several different types of tumors including breast (16,17), colon (18), bladder (19), and gastric cancer (20,21). Rac1 overexpression was observed in metastatic gastric (21), breast (15), prostate (22), bladder upper urinary tract cancer (19). Rac1 promoted prostate cancer progression and recurrence upon activation by VAV3, a GEF for Rac1 activation (14).…”

Section: Introductionmentioning

confidence: 99%

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Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

Feng

Shi

et al. 2015

International Journal of Oncology

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Abstract. Rac1 is a member of the Rho GTPase family. Rac1 activity is critical in regulating cytoskeleton organization and thus, modulates a diverse spectrum of cellular functions in normal and malignant cells. The aims of the present study were to investigate the expression pattern and clinical significance of Rac1, as well as the role of Rac1 in gastric cancer tumorigenesis and metastasis. The expression of Rac1 in human gastric cancer was explored by immunohistochemistry. The correlation of Rac1 expression with the clinicopathological characteristics and the survival of patients were analyzed by Pearson's Chi-square and KaplanMeier analyses, respectively. Rac1 overexpression cell model was used to examine in vitro and in vivo effects of Rac1 in cell growth, migration and invasion. Rac1 was highly expressed in gastric cancer tissues and correlated with differentiation, local invasion, lymph node metastasis and Lauren's classification. Rac1 expression in gastric cancer predicted shorter survival. Overexpression of Rac1 in gastric cancer cells dramatically induced Rac1 activation and rendered a more aggressive phenotype such as increased cell growth and migration/invasion in vitro and in vivo. Inhibiting Rac1 activity by specific inhibitor abrogated the effects of Rac1 on the malignant phenotype. Our clinical findings demonstrated that Rac1 was well correlated with aggressiveness and a negative prognostic factor. In addition, our data on experimental cell models supported the fundamental role of Rac1 in gastric cancer. Given its pivotal role in gastric tumorigenesis and progression, Rac1 can serve as a promising therapeutic target for gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

Feng

Shi

et al. 2015

International Journal of Oncology

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“…PAKs are subdivided into two groups based on structural and functional features 28,29 ; group-1 consists of PAK1, PAK2 and PAK3, while group-2 consists of PAK4, PAK5 and PAK6. Although PAK1 has been implicated in the recurrence of urothelial cancer of the bladder 30 and progression of upper tract urothelial cancer 31 , the role of other PAKs have not been well characterised in urothelial oncogenesis.…”

Section: Introductionmentioning

confidence: 99%

PAK5 mediates cell: cell adhesion integrity via interaction with E-cadherin in bladder cancer cells

Ismail

Halaçlı

Babteen

et al. 2017

Biochemical Journal

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Urothelial bladder cancer is a major cause of morbidity and mortality worldwide, causing an estimated 150,000 deaths per year. Whilst non-muscle-invasive bladder tumours can be effectively treated, with high survival rates, many tumours recur, and some will progress to muscle-invasive disease with a much poorer long term prognosis. Thus there is a pressing need to understand the molecular transitions occurring within the progression of bladder cancer to an invasive disease. Tumour invasion is often associated with a down regulation of E-cadherin expression concomitant with a suppression of cell: cell junctions and decreased levels of E-cadherin expression have been reported in higher grade urothelial bladder tumours. We find that expression of E-cadherin in a panel of bladder cancer cell lines correlated with the presence of cell: cell junctions and the level of PAK5 expression. Interestingly exogenous PAK5 has recently been described to be associated with cell: cell junctions and we now find that endogenous PAK5 is localised to cell junctions and interacts with an E-cadherin complex. Moreover, depletion of PAK5 expression significantly reduced junctional integrity. These data suggest a role for PAK5 in maintaining junctional stability and we find that in both our own patient samples and a commercially available datasets that PAK5mRNA levels are reduced in human bladder cancer compared to normal controls. Taken together this study proposes that PAK5 expression levels could be used as a novel prognostic marker for bladder cancer progression. PAK5 mediates cell: cell adhesion integrity via interaction with E-cadherin in bladder cancer cells AbstractUrothelial bladder cancer is a major cause of morbidity and mortality worldwide, causing an estimated 150,000 deaths per year. Whilst non-muscle-invasive bladder tumours can be effectively treated, with high survival rates, many tumours recur, and some will progress to muscle-invasive disease with a much poorer long term prognosis. Thus there is a pressing need to understand the molecular transitions occurring within the progression of bladder cancer to an invasive disease. Tumour invasion is often associated with a down regulation of E-cadherin expression concomitant with a suppression of cell: cell junctions and decreased levels of Ecadherin expression have been reported in higher grade urothelial bladder tumours.We find that expression of E-cadherin in a panel of bladder cancer cell lines correlated with the presence of cell: cell junctions and the level of PAK5 expression.Interestingly exogenous PAK5 has recently been described to be associated with cell: cell junctions and we now find that endogenous PAK5 is localised to cell junctions and interacts with an E-cadherin complex. Moreover, depletion of PAK5 expression significantly reduced junctional integrity. These data suggest a role for PAK5 in maintaining junctional stability and we find that in both our own patient samples and a commercially available datasets that PAK5mRNA levels are reduced in human bladder c...

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“…The results indicated that the expression of these proteins in tumor samples was significantly higher than non-tumoric samples, and it was also reported that expression of Rho, Rac1 and cdc42 proteins in advanced stages of cancer is higher than in the early stages of cancer [34]. Expression of Rac1 and PAK proteins, a potent effector of Rac1, was evaluated on four groups including tumor and non-tumoric tissue, metastatic and normal lymph nodes in the upper urinary tract cancer and the results showed that expression levels of active Rac1 and PAK in tumor and metastatic lymph nodes were significantly higher than their levels in samples non-tumoric [35]. Considering that active Rac1 can mediate looseness of adhesion connections and subsequently accelerate migratory phenotype [13,14].…”

Section: Discussionmentioning

confidence: 99%

Effect of Quercetin on RAC1 Gene Expression as a Marker of Metastasis in Cervical Cancer Cells

Chakerzehi

Arvanagh

Saedi

et al. 2015

Zahedan J Res Med Sci

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Background: Cancer metastasis is the most important cause of cancer death and different treatment strategies have targeted on preventing the occurrence of metastasis. Quercetin is a flavonoid and widely used as an antioxidant and recent studies have discovered its anticancer and antiproliferative capabilities. Rac1 is protein known to involve in tumor invasion and metastases. Objectives: In this study, we investigated the effect of quercetin on expression of Rac1 protein. Materials and Methods:In this experimental study, HeLa cells were treated with quercetin at 2 concentrations (20 and 40 μM) for 24 hours and then cell lysate was assessed by Western blotting analysis to investigate the impact of quercetin on expression of Rac1 protein.Results: Quercetin significantly decreased Rac1 expression of HeLa cells assessed by western blotting, in dose-dependent manners (P < 0.05). Conclusions: This study showed that quercetin decreased Rac1 expression as a marker of metastasis in cervical cancer cells. Therefore, the quercetin may provide an effective new strategy to reduce of tumor metastasis.

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Increased Rac1 activity and Pak1 overexpression are associated with lymphovascular invasion and lymph node metastasis of upper urinary tract cancer

Cited by 71 publications

References 27 publications

Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

Rac1 is correlated with aggressiveness and a potential therapeutic target for gastric cancer

PAK5 mediates cell: cell adhesion integrity via interaction with E-cadherin in bladder cancer cells

Effect of Quercetin on RAC1 Gene Expression as a Marker of Metastasis in Cervical Cancer Cells

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