Nuclear expression of S‐phase kinase–associated protein 2 predicts poor prognosis of hepatocellular carcinoma

Shin, Eak Kyun; Kim, Soo Hee; Jeong, Hae Yeon; Jang, Ja June; Lee, Kyuho

doi:10.1111/j.1600-0463.2011.02838.x

Cited by 17 publications

(15 citation statements)

References 26 publications

(37 reference statements)

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“…Emerging evidence has demonstrated that Skp2 serves a critical role in the development of liver cancer. For example, the nuclear expression of Skp2 predicted poor prognosis in patients with liver carcinoma (22). In addition, the inhibition of Skp2 induced apoptosis and inhibited cell proliferation in liver carcinoma cells via the upregulation of cyclin dependent kinase inhibitor 1B (p27) (23).…”

Section: Discussionmentioning

confidence: 99%

Paeoniflorin inhibits cell viability and invasion of liver cancer cells via inhibition of Skp2

et al. 2020

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Paeoniflorin (PF) has been demonstrated to exert tumor suppressive functions in various types of human cancer. However, the mechanisms of PF-mediated anti-tumor activity have not been fully elucidated. S-phase kinase associated protein 2 (Skp2) has been characterized as an oncoprotein that contributes to carcinogenesis. Therefore, the inhibition of Skp2 may be a useful approach for the treatment of various types of human cancer. The present study explored whether PF inhibited the expression of Skp2 in liver cancer cells, leading to cell viability inhibition, induction of apoptosis, and suppression of migration and invasion. PF treatment led to inhibition of Skp2 expression in liver cancer cells. The overexpression of Skp2 abolished PF-mediated anti-cancer activity, whereas the downregulation of Skp2 enhanced this type of activity. The data indicated that PF may be considered as a novel inhibitor of Skp2 in liver cancer cells.

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Section: Discussionmentioning

confidence: 99%

Paeoniflorin inhibits cell viability and invasion of liver cancer cells via inhibition of Skp2

et al. 2020

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“…Indeed Skp2 is found to be overexpressed in oral squamous cell carcinoma and ER‐negative breast carcinoma . Recent studies suggest that Skp2 is also upregulated in hepatocellular carcinoma and is linked to poor prognosis . (Also refer to Table for other SCF ubiquitin ligases)…”

Section: Ubiquitin Ligases Targeting P53mentioning

confidence: 99%

A portrayal of E3 ubiquitin ligases and deubiquitylases in cancer

Satija

Bhardwaj

Das

2013

Intl Journal of Cancer

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E3 ubiquitin ligases and deubiquitylating enzymes (DUBs) are the key components of ubiquitin proteasome system which plays a critical role in cellular protein homeostasis. Any shortcoming in their biological roles can lead to various diseases including cancer. The dynamic interplay between ubiquitylation and deubiquitylation determines the level and activity of several proteins including p53, which is crucial for cellular stress response and tumor suppression pathways. In this review, we describe the different types of E3 ubiquitin ligases including those targeting tumor suppressor p53, SCF ligases and RING type ligases and accentuate on biological functions of few important E3 ligases in the cellular regulatory networks. Tumor suppressor p53 level is tightly regulated by multiple E3 ligases including Mdm2, COP1, Pirh2, etc. SCF ubiquitin ligase complexes are key regulators of cell cycle and signal transduction. BRCA1 and VHL RING type ligases function as tumor suppressors and play an important role in DNA repair and hypoxia response respectively. Further, we discuss the biological consequences of deregulation of the E3 ligases and the implications for cancer development. We also describe deubiquitylases which reverse the process of ubiquitylation and regulate diverse cellular pathways including metabolism, cell cycle control and chromatin remodelling. As the E3 ubiquitin ligases and DUBs work in a substrate specific manner, an improved understanding of them can lead to better therapeutics for cancer.Cancer is best characterized at molecular level either by gainof-function of oncoproteins and/or loss-of-function of tumor suppressor proteins. The turnover and the biological activity of several oncoproteins and tumor suppressors is governed by the ubiquitin proteasome system (UPS). The UPS comprises two distinct steps: the covalent attachment of multiple ubiquitin molecules to the protein substrate and degradation of the polyubiquitylated protein by the 26S proteasome complex. 1 A ubiquitin molecule consists of a highly conserved 76-amino-acid polypeptide that is conjugated through an isopeptide linkage to other proteins. Key structural features of ubiquitin include its b-grasp fold, its C-terminal tail and seven lysine residues through which polyubiquitin chains are linked. The most important lysine residues of ubiquitin are K48 and K63. K48-linked polyubiquitylation targets the protein for proteasomal degradation while linear ubiquitin chains, monoubiquitylation and K63-linked polyubiquitylation play a role in signalling.The first step of UPS is cascaded by at least three enzymes: the ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2 and ubiquitin ligase E3. A role for E1 in cancer has not been described, and only a few reports have correlated E2 to tumorigenesis. 2 In contrast, cumulative evidence suggests alterations in the activity of many E3 ligases in the etiology of cancer development. 3,4 Because E3 ligases are the recognition element of the system, thus by providing the substrate specificit...

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“…Such an imbalance leads to pRB hyperphosphorylation and rise in E2F1-DP1 complexes, which activate DNA synthesis genes and allow the transition from the G1 to the S phase of the cell cycle in these lesions [ 4 - 8 ]. Although gene silencing by promoter hypermethylation seems to play a major role in the inactivation of tumor suppressor genes in liver cancer [ 9 - 11 ], emerging evidence indicates a post-transcriptional regulation of cell cycle negative modulators by the S-phase kinase-associated protein 1 (SKP1)/CUL1/F-box protein (SCF) complex, an ubiquitin ligase implicated in the G1-S transition regulation, in this tumor type [ 12 - 15 ]. The pro-oncogenic activity of the SCF complex in various tumors, including HCC, seems to reside in its ability to induce the proteasomal degradation of several inhibitors of the cell cycle, including p27 KIP1 , p57 KIP2 , DUSP1, and RASSF1A [ 16 - 21 ].…”

Section: Introductionmentioning

confidence: 99%

“…In particular, S-phase kinase-associated protein 2 (SKP2), a main member of the SCF complex, is almost ubiquitously overexpressed in cancer and considered to be a bona fide oncogene due to its transforming abilities in vitro and in vivo [ 16 - 21 ]. Previously, others and we have demonstrated that SKP2 is upregulated in rodent and human HCC [ 12 - 15 ]. In addition, it has been shown that SKP2 nuclear accumulation directly correlates with clinical aggressiveness of HCC and is associated with shorter survival of liver cancer patients [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

SKP2 cooperates with N-Ras or AKT to induce liver tumor development in mice

et al. 2014

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Mounting evidence indicates that S-Phase Kinase-Associated Protein 2 (SKP2) is overexpressed in human hepatocellular carcinoma (HCC). However, the role of SKP2 in hepatocarcinogenesis remains poorly delineated. To elucidate the function(s) of SKP2 in HCC, we stably overexpressed the SKP2 gene in the mouse liver, either alone or in combination with activated forms of N-Ras (N-RasV12), AKT1 (myr-AKT1), or β-catenin (ΔN90-β-catenin) protooncogenes, via hydrodynamic gene delivery. We found that forced overexpression of SKP2, N-RasV12 or ΔN90-β-catenin alone as well as co-expression of SKP2 and ΔN90-β-catenin did not induce liver tumor development. Overexpression of myr-AKT1 alone led to liver tumor development after long latency. In contrast, co-expression of SKP2 with N-RasV12 or myr-AKT1 resulted in early development of multiple hepatocellular tumors in all SKP2/N-RasV12 and SKP2/myr-AKT1 mice. At the molecular level, preneoplastic and neoplastic liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice exhibited a strong induction of AKT/mTOR and Ras/MAPK pathways. Noticeably, the tumor suppressor proteins whose levels have been shown to be downregulated by SKP2-dependent degradation in various tumor types, including p27, p57, Dusp1, and Rassf1A were not decreased in liver lesions from SKP2/N-RasV12 and SKP2/myr-AKT1 mice. In human HCC specimens, nuclear translocation of SKP2 was associated with activation of the AKT/mTOR and Ras/MAPK pathways, but not with β-catenin mutation or activation. Altogether, the present data indicate that SKP2 cooperates with N-Ras and AKT proto-oncogenes to promote hepatocarcinogenesis in vivo.

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Nuclear expression of S‐phase kinase–associated protein 2 predicts poor prognosis of hepatocellular carcinoma

Cited by 17 publications

References 26 publications

Paeoniflorin inhibits cell viability and invasion of liver cancer cells via inhibition of Skp2

Paeoniflorin inhibits cell viability and invasion of liver cancer cells via inhibition of Skp2

A portrayal of E3 ubiquitin ligases and deubiquitylases in cancer

SKP2 cooperates with N-Ras or AKT to induce liver tumor development in mice

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