Study of the correlation between H-ras mutation and primary hepatocellular carcinoma

Sui, Guode; Ma, Xiang; Liu, Shiguo; Niu, Haitao; Dong, Qi

doi:10.3892/ol.2012.832

Cited by 13 publications

(10 citation statements)

References 14 publications

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“…RAS mutations did not seem to play an important role in HCC carcinogenesis in Black Africans (Leon and Kew, 1995). Even though the mutations of RAS family genes are infrequent in Asian population (1.7-5.6% K-RAS, 0% B-RAF, 0-71% H-RAS (Harvey rats sarcoma), 0% N-RAS (rats sarcoma neuroblastoma homolog)) (Hou et al, 2014;Taketomi et al, 2013;Zuo et al, 2012;Sui et al, 2012), mutation rate seems to be higher in Western population (2-16% K-RAS, 0-23% B-RAF, 14% N-RAS) (Janku et al, 2014;Stork et al, 1991;Colombino et al, 2012;Tannapfel et al, 2003). One of the highest rate of K-RAS mutation (42%) has been described in Western workers exposed to vinyl chloride, which seems to have a direct toxic effect in the hepatocytes (Weihrauch et al, 2001).…”

Section: Ras/raf/mek/erk Pathwaymentioning

confidence: 99%

Hepatocellular carcinoma: Exploring the impact of ethnicity on molecular biology

Lamarca

Mendiola²,

Barriuso

2016

Critical Reviews in Oncology/Hematology

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Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer-related death. The high rate of diagnosis in non-curable stages and the lack of novel active treatments make it necessary to review all the possible sources of misleading results in this scenario. The incidence of HCC shows clear geographical variation with higher annual incidence in Asia and Africa than in Western countries; we aimed to review the literature to find if there are different trends in the main activated molecular pathways. Hyperactivation of RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signalling and epithelial to mesenchymal transition (EMT) process are more prevalent in the Western population; however, fibroblast growth factor (FGF), transforming growth factor β (TGFβ) and Notch pathways seems to be more relevant in Asian population. Whether these variations just reflect the distinct distribution of known causes of HCC or proper ethnical differences remain to be elucidated. Nevertheless, these clearly different patterns are relevant to regional or worldwide clinical trial design. If this information is neglected by sponsors and researchers the rate of failure in HCC trials will not improve.

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Section: Ras/raf/mek/erk Pathwaymentioning

confidence: 99%

Hepatocellular carcinoma: Exploring the impact of ethnicity on molecular biology

Lamarca

Mendiola²,

Barriuso

2016

Critical Reviews in Oncology/Hematology

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“…All experiments conformed to the Animal Care and use Guidelines of the Institute for Nutritional Sciences (Shanghai, China). Briefly, 4-to 6-week old female BALB/c athymic nude mice were obtained from Shanghai Experimental Animal Center (Shanghai, China) and subcutaneously injected with a suspension containing 5x10 6 negative control and H1-siRNA and H2-siRNA transfected cells. One week after cell implantation, DDP (4 mg/kg) was injected intraperitoneally into the tumor-bearing mice every 4 days for 3 weeks (between days 8 and 31).…”

Section: Construction Of the H-ras Shrna Vector And Gene Transfectionmentioning

confidence: 99%

“…As a result, Ras mutations can lead to the production of permanently activated Ras oncoprotein, which occurs in ~30% of all human cancers (4,5). In HCC, a recent study showed that H-Ras mutation was present in 49/69 (71.01%) of HCC patient samples (6). Overall, the mutated Ras protein leads to uncontrolled cell proliferation and resistance to apoptosis signals (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

“…In HCC, a recent study showed that H-Ras mutation was present in 49/69 (71.01%) of HCC patient samples (6). Overall, the mutated Ras protein leads to uncontrolled cell proliferation and resistance to apoptosis signals (4)(5)(6). Thus far, Ras family members that have been reported to be mutated in different types of cancer include K-Ras in pancreatic, nonsmall cell lung and colorectal cancer and seminoma; N-Ras in melanoma, HCC, myelodysplastic syndrome and acute myelogenous leukemia; and H-Ras in follicular and undifferentiated papillary thyroid, bladder and renal cell cancer (7).…”

Section: Introductionmentioning

confidence: 99%

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Knockdown of mutated H-Ras V12 expression induces chemosensitivity of hepatocellular carcinoma cells to cisplatin treatment in vitro and in nude mouse xenografts

et al. 2014

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Ras mutations contribute to human cancer development. The present study assessed the Ras V12 mutation in hepatocellular carcinoma (HCC) cells and the role of its silencing in vitro and in nude mouse xenografts. HCC BEL7402 cells expressed mutations of V12 (Val/Gly) and wild-type H-Ras, whereas SMMC7721 cells only expressed wild-type H-Ras. The shRNA constructs specifically silenced mutated H-Ras expression in BEL7402 cells, but did not affect wild-type Ras expression in SMMC7721 cells. Silencing of mutated H-Ras expression reduced BEL7402 cell viability, induced apoptosis and arrested cells at the G0/G1 phase of the cell cycle. Expression of phospho-Akt was also significantly decreased, while several apoptotic proteins were also activated. Furthermore, sensitivity of stably H1-shRNA and H2-shRNA transfected BEL7402 cells to cisplatin treatment was increased by 7.19- and 5.39-fold, respectively, compared to that in the negative control cells, and apoptosis-related gene expression was also altered. Intraperitoneal administration of cisplatin led to a substantial reduction in HCC xenograft growth by 81 and 77% in the H1-shRNA and H2-shRNA transfected tumor xenografts, respectively, compared to a 37% reduction in mice bearing negative control tumor cells. These data demonstrate that knockdown of mutated H-Ras V12 expression induced chemosensitivity of HCC cells to cisplatin treatment in vitro and in vivo.

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“…Reduced expression or silencing of the GAPs causes increase in the levels of the GTP-bound active form of the Ras protein, leading to activated Ras-signaling in HCC. Interestingly, another study with 69 Chinese patients demonstrated mutations in H-Ras, codons 40 and 61, in about 71% of the patients (5). …”

Section: Introductionmentioning

confidence: 99%

Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features

Kopanja

Pandey

Kiefer

et al. 2015

Journal of Hepatology

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Background & Aims Over-expression of FoxM1 correlates with poor prognosis in hepatocellular carcinoma (HCC). Moreover, the Ras-signaling pathway is found to be ubiquitously activated in HCC through epigenetic silencing of the Ras-regulators. We investigated the roles of FoxM1 in Ras-driven HCC, and on HCC cells with stem-like features. Methods We employed a transgenic mouse model that expresses the oncogenic Ras in the liver. That strain was crossed with a strain that harbor floxed alleles of FoxM1 and the MxCre gene that allows conditional deletion of FoxM1. FoxM1 alleles were deleted after development of HCC, and the effects on the tumors were analyzed. Also, FoxM1-siRNA was used in human HCC cell lines to determine its role in the survival of the HCC cells with stem cell features. Results Ras-driven tumors over-express FoxM1. Deletion of FoxM1 inhibits HCC progression. There was increased accumulation of reactive oxygen species (ROS) in the FoxM1-deleted HCC cells. Moreover, FoxM1-deletion caused a disproportionate loss of the CD44+ and EpCAM+ HCC cells in the tumors. We show that FoxM1 directly activates expression of CD44 in human HCC cells. Moreover, the human HCC cells with stem cell features are addicted to FoxM1 for ROS-regulation and survival. Conclusion Our results provide genetic evidence for an essential role of FoxM1 in the progression of Ras-driven HCC. In addition, FoxM1 is required for the expression of CD44 in HCC cells. Moreover, FoxM1 plays a critical role in the survival of the HCC cells with stem cell features by regulating ROS.

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Study of the correlation between H-ras mutation and primary hepatocellular carcinoma

Cited by 13 publications

References 14 publications

Hepatocellular carcinoma: Exploring the impact of ethnicity on molecular biology

Hepatocellular carcinoma: Exploring the impact of ethnicity on molecular biology

Knockdown of mutated H-Ras V12 expression induces chemosensitivity of hepatocellular carcinoma cells to cisplatin treatment in vitro and in nude mouse xenografts

Essential roles of FoxM1 in Ras-induced liver cancer progression and in cancer cells with stem cell features

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