Upregulation of Rac GTPase-Activating Protein 1 Is Significantly Associated with the Early Recurrence of Human Hepatocellular Carcinoma

Wang, Suk Mei; Ooi, London Lucien Peng Jin; Hui, Kam M.

doi:10.1158/1078-0432.ccr-11-0557

Cited by 137 publications

(135 citation statements)

References 34 publications

(36 reference statements)

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“…Additionally, we consider one of the reasons for this discrepancy is that RACGAP1 has twenty-nine splice variants, and the primer for RACGAP1 described by Ke HL et al [7] used in the present study detects most splice variants. RacGAP1 is reportedly associated with more aggressive cancer phenotypes of high-grade breast cancer [26], epithelial ovarian cancer [27], and hepatocellular carcinoma [15] in the transition from low invasive to high invasive disease. In subgroup analysis of 113 patients with diffuse type gastric cancer, we observed that RacGAP1 IHC scores in patients with lymph node metastasis and vascular invasion were significantly higher than scores in patients without them (cut-off: median value.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, RacGAP1 is involved in cell transformation, motility, migration, and metastasis [9][10][11][12]. The clinical significance of RacGAP1 has been reported in several malignancies such as meningioma, breast cancer, and hepatocellular carcinoma [7,8,[13][14][15]. The previous studies suggested that high RacGAP1 expression reflected increased aggressiveness of the tumor.…”

Section: Introductionmentioning

confidence: 99%

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Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

et al. 2014

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Background Rac GTPase activating protein 1 (RacGAP1) plays a regulatory role in cell growth, transformation and metastasis. The aim of this study was to clarify the association between RacGAP1 expression and clinical outcome in patients with gastric cancer. Methods A total of 232 gastric cancer patients in our institute who underwent surgery without preoperative treatments were enrolled in this study. We investigated RacGAP1 expression using immunohistochemistry (IHC) and evaluated IHC scores calculated by the percentage of positive cells and intensity and its expression at the invasive front. RACGAP1 expression was also assessed. Results RacGAP1 expression was observed in the nuclei of gastric cancer cells. Evaluation by IHC score showed no significant correlations with clinicopathological variables except for histological differentiation. In transcriptional analyses, RACGAP1 expression was elevated in diffuse type gastric cancer than intestinal type without a significant difference. We observed significant correlations of Rac-GAP1 protein expression at the invasive front with older age, tumor size, lymph node metastasis, lymphatic invasion, vascular invasion and advanced stage. Patients with RacGAP1 protein expression at the invasive front had significantly poorer prognosis than those without it (P \ 0.0001). In multivariate analysis, lymph node metastasis, distant metastasis and positive RacGAP1 expression at the invasive front were independent prognostic factors (lymph node metastasis: P = 0.0106; distant metastasis: P = 0.0012; RacGAP1: P = 0.0011). Conclusions RacGAP1 expression at the invasive front in gastric cancer was significantly correlated with factors reflecting tumor progression and poor prognosis. Our data suggest that RacGAP1 might play important roles in the progression of gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

et al. 2014

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“…PRC1 has been shown to overexpress in various cancers including breast cancer (8), bladder cancer (9), hepatocellular carcinoma (10,11) and pancreatic cancer (12). The previous study (13) showed that PRC1 was up-regulated in primary gastric cancers and overexpression of PRC1 in gastric cancers was associated with poor disease-specific survival and OS.…”

Section: Original Articlementioning

confidence: 99%

Protein regulator of cytokinesis-1 expression: prognostic value in lung squamous cell carcinoma patients

Zhan

Liu

et al. 2017

J. Thorac. Dis.

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Background: Protein regulator of cytokinesis-1 (PRC1) has been shown to participate in the completion of cytokinesis, and it is dysregulated in cancer processes. However, its relevance in lung squamous cell carcinoma (SCC) remained largely unknown. We aimed to study the expression pattern of PRC1 and assess its clinical significance in lung SCC.Methods: PRC1 protein expression in human lung SCC and adjacent normal lung tissues was detected by immunohistochemistry. PRC1 expression was assessed in association with clinicopathological features and clinical outcomes of lung SCC patients. Results: In lung SCC tissues, PRC1 protein expression was significantly higher than those in paired normal lung tissues. The lung SCC patients with PRC1 overexpression had an advanced pathological stage (TNM stage), positive lymph node metastasis, and a shorter overall survival (OS) time more frequently than patients with low PRC1 expression. Additional, PRC1 expression was also shown to be poor as a prognostic factor for OS in patients with lung SCC. Conclusions: Our study indicated that aberrant expression of PRC1 may point to biochemical recurrence in lung SCC. This highlights its potential as a valuable prognostic marker for lung SCC.

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“…There is an existing literature showing that the PI3K/AKT pathway is an important component of RacGAP1 signaling (38). However, whether PI3K/AKT signaling lies upstream or downstream of the Rho family of GTPases remains less clear and appears to be context-specific (38).…”

Section: Racgap1 Modulates Doxorubicin Sensitivity Via Downstream Actmentioning

confidence: 99%

“…However, whether PI3K/AKT signaling lies upstream or downstream of the Rho family of GTPases remains less clear and appears to be context-specific (38). Dysregulation of the PI3K/ AKT pathway is a common event in HNSCC, which can be attributed to multiple factors, such as mutations, amplifications, and signal-induced activation of the pathway (39).…”

Section: Racgap1 Modulates Doxorubicin Sensitivity Via Downstream Actmentioning

confidence: 99%

RacGAP1 Is a Novel Downstream Effector of E2F7-Dependent Resistance to Doxorubicin and Is Prognostic for Overall Survival in Squamous Cell Carcinoma

Hazar-Rethinam

Long

Gannon

et al. 2015

Molecular Cancer Therapeutics

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We have previously shown that E2F7 contributes to drug resistance in head and neck squamous cell carcinoma (HNSCC) cells. Considering that dysregulation of responses to chemotherapy-induced cytotoxicity is one of the major reasons for treatment failure in HNSCC, identifying the downstream effectors that regulate E2F7-dependent sensitivity to chemotherapeutic agents may have direct clinical impact. We used transcriptomic profiling to identify candidate pathways that contribute to E2F7-dependent resistance to doxorubicin. We then manipulated the expression of the candidate pathway using overexpression and knockdown in in vitro and in vivo models of SCC to demonstrate causality. In addition, we examined the expression of E2F7 and RacGAP1 in a custom tissue microarray (TMA) generated from HNSCC patient samples. Transcriptomic profiling identified RacGAP1 as a potential mediator of E2F7-dependent drug resistance. We validated E2F7-dependent upregulation of RacGAP1 in doxorubicininsensitive SCC25 cells. Extending this, we found that selective upregulation of RacGAP1 induced doxorubicin resistance in previously sensitive KJDSV40. Similarly, stable knockdown of RacGAP1 in insensitive SCC25 cells induced sensitivity to doxorubicin in vitro and in vivo. RacGAP1 expression was validated in a TMA, and we showed that HNSCCs that overexpress RacGAP1 are associated with a poorer patient overall survival. Furthermore, E2F7-induced doxorubicin resistance was mediated via RacGAP1-dependent activation of AKT. Finally, we show that SCC cells deficient in RacGAP1 grow slower and are sensitized to the cytotoxic actions of doxorubicin in vivo. These findings identify RacGAP1 overexpression as a novel prognostic marker of survival and a potential target to sensitize SCC to doxorubicin.

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Upregulation of Rac GTPase-Activating Protein 1 Is Significantly Associated with the Early Recurrence of Human Hepatocellular Carcinoma

Cited by 137 publications

References 34 publications

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

Protein regulator of cytokinesis-1 expression: prognostic value in lung squamous cell carcinoma patients

RacGAP1 Is a Novel Downstream Effector of E2F7-Dependent Resistance to Doxorubicin and Is Prognostic for Overall Survival in Squamous Cell Carcinoma

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