Identification of p46 Shc expressed in the nuclei of hepatocytes with high proliferating activity: Study of regenerating rat liver

Jin, Yuji; Masaki, Tsutomu; Yoshida, Shuhei; Kita, Yuko; Han, Feng; Uchida, Naoshige; Yoshiji, Hitoshi; Kitanaka, Akira; Watanabe, Seishiro; Kurokohchi, Kazutaka; Kuriyama, Shigeki

doi:10.3892/ijmm.13.5.721

Cited by 6 publications

(7 citation statements)

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“…In our previous study of spontaneous hepatocarcinogenesis in the Long‐Evans Cinnamon rat, we showed that total activated Shc (p46‐ and p52‐Shc) was highly increased in hepatoma cells, with a prominent activation of p46‐Shc in HCC specimens . We could also demonstrate that p46‐Shc was strongly up‐regulated in the early stage of liver regeneration in rats with 70% hepatectomy, supporting its role also as a primary inducer of hepatocyte regeneration . At present, it is unclear why only phosphorylated p46Shc is up‐regulated during proliferation.…”

Section: Discussionmentioning

confidence: 53%

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Sublethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma

et al. 2013

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Radiofrequency ablation (RFA) is a potentially curative therapy for hepatocellular carcinoma (HCC). However, incomplete RFA can induce accelerated invasive growth at the periphery. The mechanisms underlying the RFA-induced tumor promotion remain largely unexplored. Three human HCC cell lines were exposed to 45 C-55 C for 10 minutes, simulating the marginal zone of RFA treatment. At 5-12 days posttreatment cell proliferation, parameters of epithelial-mesenchymal transition (EMT), and activation of mitogen-activated protein kinases were analyzed. Livers from patients with viral hepatitis without and with HCC (n 5 114) were examined to confirm the relevance of altered kinase patterns. In vivo tumorigenic potential of heat-treated versus untreated HCC cells was studied in nude mice. Heating to 55 C killed all HCC cells, whereas 65%-85% of cells survived 48 C-50 C, developing spindle-like morphology and expressing CD133, cytokeratin (CK)7, CK19, procollagen-a1(I), and Snail at day 5 after heat exposure, which returned to baseline at day 12. Heat-exposed HCC cells showed enhanced proliferation and prominent activation of p46-Shc (Src homology and collagen) and downstream extracellular signalrelated kinase (Erk)1/2. In patients, Shc expression correlated with malignant potential and overall survival. Blocking Erk1/2 reduced proliferation and EMT-like changes of heat-treated HCC cells. Implantation of heat-exposed HEPG2 cells into nude mice induced significantly larger, more aggressive tumors than untreated cells. Conclusions: Sublethal heat treatment skews HCC cells toward EMT and transforms them to a progenitor-like, highly proliferative cellular phenotype in vitro and in vivo, which is driven significantly by p46Shc-Erk1/2. Suboptimal RFA accelerates HCC growth and spread by transiently inducing an EMT-like, more aggressive cellular phenotype. (HEPATOLOGY 2013;58:1667-1680 R adiofrequency ablation (RFA) is accepted as a potentially curative therapy for the early stages of primary hepatocellular carcinoma (HCC). 1 RFA induces tumor necrosis with low complication rates and is superior to percutaneous ethanol injection in tumor ablation.2 However, suboptimal RFA treatment for HCC has been reported as a risk factor of early diffuse recurrence.3 Large tumor size is a major risk factor of Abbreviations: 7-AAD, 7-aminoactinomycin D; AFP, alpha-fetaprotein; ALB, albumin; BSA, bovine serum albumin; CFSE, carboxyfluorescein succinimidyl ester; CHC, chronic hepatitis C; CK, cytokeratin; COL1A1, type I procollagen; Ct, cycle threshold; DI, division indices; DMEM, Dulbecco's modified Eagle's medium; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transition; Erk, extracellular signal-related kinase; ETW, estimated tumor weight; FACS, fluorescein-activated cell sorting; FBS, fetal bovine serum; FCM, flow cytometry; FGFR, fibroblast growth factor receptor; HCC, hepatocellular carcinoma; HSP, heat shock protein; IGF-1R, insulin-like growth factor 1 receptor; JNK, c-Jun N-terminal kinase; LI, labeling indices; MAP...

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Section: Discussionmentioning

confidence: 53%

“…However, the role of Shc isoforms in liver diseases is still poorly understood. Although we previously reported that p46‐Shc phosphorylation is a hallmark of hepatocarcinogenesis and liver regeneration in rats, the role of Shc in human HCC has not been studied yet.…”

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confidence: 98%

Sublethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma

et al. 2013

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“…Furthermore, although previous studies have indicated that p66 antagonizes the growth stimulatory effects of p52, relatively little is known about the biology of these proteins in benign proliferation in the liver. One study in which proliferation was induced by PH reported a marked increase in p46 levels in regenerating rat livers . Conversely, p66 appears to act as a ‘brake’ for proliferative processes, and impaired regeneration after PH in aged mice has been linked to enhanced oxidative stress and increased apoptosis mediated by p66 .…”

Section: Discussionmentioning

confidence: 99%

“…One study in which proliferation was induced by PH reported a marked increase in p46 levels in regenerating rat livers. 52 Conversely, p66 appears to act as a 'brake' for proliferative processes, and impaired regeneration after PH in aged mice has been linked to enhanced oxidative stress and increased apoptosis mediated by p66. 53 Further studies will be required to confirm this relationship, but taken together with our data, these observations suggest that p46 and p52 may be involved in benign proliferation of hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Tumour promotion versus tumour suppression in chronic hepatic iron overload

Bloomer

Brown

2015

Cell Biochemistry & Function

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Although iron-catalysed oxidative damage is presumed to be a major mechanism of injury leading to cirrhosis and hepatocellular carcinoma in hemochromatosis, these events have been difficult to recapitulate in an animal model. In this study, we evaluated regulators of hepatocarcinogenesis in a rodent model of chronic iron overload. Sprague-Dawley rats were iron loaded with iron dextran over 6 months. Livers were harvested and analysed for markers of oxidative stress, as well as the following proteins: p53, murine double minute 2, the Shc proteins p66, p52, p46; β-catenin, CHOP, C/EBPα and Yes-associated protein. In this model, iron loading is associated with hepatocyte proliferation, and indices of oxidative damage are mildly increased in tandem with augmented antioxidant defenses. Alterations potentially favouring carcinogenesis included a modest but significant decrease in p53 levels and increases in p52, p46 and β-catenin levels compared with control livers. Countering these factors, the iron-loaded livers demonstrated a significant decrease in CHOP, which has recently been implicated in the development of hepatocellular carcinoma, as well as a reciprocal increase in C/EBPα and decrease in Yes-associated protein. Our results suggest that chronic iron overload elicits both tumour suppressive as well as tumour-promoting mechanisms in rodent liver.

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“…p52 Shc is known to be active survival and proliferative signals through growth factor-dependent Ras recruitment and activation [41] , and p46 Shc seems to show its function in the nuclear [42] . p52 Shc is known to be active survival and proliferative signals through growth factor-dependent Ras recruitment and activation [41] , and p46 Shc seems to show its function in the nuclear [42] .…”

Section: P66 Shc Mediates Anoikis By Activation Of Rhoamentioning

confidence: 99%

Cellular anchorage sensing and anoikis

Zheng

Zhe

et al. 2011

Clin. Oncol. Cancer Res.

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Normal epithelial cells that lose the integrindependent anchorage to their extracellular matrix trigger anoikis, while metastatic tumor cells bypass anoikis pathway, which is one of the key events to achieve the metastasis. Physiological role of anoikis is also involved during embryonic development and tissue homeostasis, suggesting that anoikis must be strictly regulated at some level. Despite its importance, the molecular pathways involved in the regulation of anoikis and the proximal signals reporting loss of anchorage are poorly understood. Recent studies suggest an adaptor protein p66 Shc , localizing at focal adhesions, mediates anoikis through activation of RhoA. However, expression of p66 Shc is inadequate in metastatic cancer cells, failing to initiate anoikis and promoting tumor metastasis. Reexpression of proapoptotic protein p66 Shc can restore the susceptibility to anoikis. Thus, p66 Shc may be a potential target molecule for diagnosis of tumor metastasis and for tumor treatment.

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Identification of p46 Shc expressed in the nuclei of hepatocytes with high proliferating activity: Study of regenerating rat liver

Cited by 6 publications

References 44 publications

Sublethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma

Sublethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma

Tumour promotion versus tumour suppression in chronic hepatic iron overload

Cellular anchorage sensing and anoikis

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