Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

Jia, Deshui; Jing, Ying; Zhang, Zhenfeng; Liu, Li; Ding, Jie; Zhao, Fangyu; Ge, Chao; Wang, Qifeng; Chen, Taoyang; Yao, Ming; Li, Jinjun; Gu, Jianren; He, Xianghuo

doi:10.1038/cr.2013.158

Cited by 66 publications

(60 citation statements)

References 61 publications

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“…A total of 144 somatic mutations were identified in the six HB tumors, including 28 somatic nonsynonymous mutations (Supporting Table S2). An average of 4.67 somatic mutations (range, 2‐8 mutations) were observed in each case, which is similar to the report of a recent meeting abstract in which 3.7 mutations per tumor were observed in 24 HB patients . Subsequently, 24 of the 28 nonsynonymous mutations (85.7%) within 21 genes were further verified in the same samples by Sanger sequencing (Fig.…”

Section: Resultssupporting

confidence: 85%

Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex

et al. 2014

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Hepatoblastoma (HB) is the most common primary liver tumor in children. Mutations in the b-catenin gene that lead to constitutive activation of the Wnt pathway have been detected in a large proportion of HB tumors. To identify novel mutations in HB, we performed whole-exome sequencing of six paired HB tumors and their corresponding lymphocytes. This identified 24 somatic nonsynonymous mutations in 21 genes, many of which were novel, including three novel mutations targeting the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) genes in the Wnt pathway, and genes previously shown to be involved in the ubiquitin ligase complex (SPOP, KLHL22, TRPC4AP, and RNF169). Functionally, both the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) were observed to be gain-of-functional mutations, and the CAPRIN2 (R968H/S969C) was also shown to activate the Wnt pathway in HB cells. These findings suggested the activation of the Wnt pathway in HB, which was confirmed by immunohistochemical staining of the b-catenin in 42 HB tumors. We further used short hairpin RNA (shRNA)-mediated interference to assess the effect of 21 mutated genes on HB cell survival. The results suggested that one novel oncogene (CAPRIN2) and three tumor suppressors (SPOP, OR5I1, and CDC20B) influence HB cell growth. Moreover, we found that SPOP S119N is a loss-of-function mutation in HB cells. We finally demonstrated that one of the mechanisms by which SPOP inhibits HB cell proliferation is through regulating CDKN2B expression. Conclusion: These results extend the landscape of genetic alterations in HB and highlight the dysregulation of Wnt and ubiquitin pathways in HB tumorigenesis.

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Section: Resultssupporting

confidence: 85%

Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex

et al. 2014

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“…In addition, using an integrated analysis of copy number and expression profiling data, one recent study found that the recurrent region of the 1q24.1-24.2 amplicon specifically targets the myelin protein zero-like protein 1 ( MPZL1 ) gene in HCC; the expression levels of MPZL1 were positively correlated with the intrahepatic metastasis of the HCC specimens[45]. …”

Section: Genomic Instabilitymentioning

confidence: 99%

“…More specifically, 8q24.21-24.22 is the most frequently amplified region in chromosome 8q, with amplification occurring in 53.4% of samples and targeting the known oncogenes myelocytomatosis viral oncogene ( MYC ), Arf-GAP with SH3 domain, ANK repeat and PH domain-containing protein 1 ( DDEF1 ), and human melanoma-derived leucine zipper extra-nuclear factor ( MLZE )[45]. MYC has been identified as a central regulator of malignant transformations in early hepatocarcinogenesis[46], and c-myc gene amplification has also been found to be significantly correlated with DFS and OS in patients with HCC after surgical resection[47].…”

Section: Genomic Instabilitymentioning

confidence: 99%

Genetic alterations in hepatocellular carcinoma: An update

Niu¹,

Niu²,

Wang³

2016

WJG

137

108

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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.

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“…The tissues were formalin-fixed and paraffin-embedded for further immunohistochemistry. In this study, the criteria to define intrahepatic metastasis were: (1) tumors obviously growing from PVTT, (2) multiple satellite nodules which are smaller than the main tumor they surround, and (3) small single tumor which is present near the main tumor with similar histology 17, 18. The study protocol was approved by the research ethics committee of Sun Yat-Sen University.…”

Section: Methodsmentioning

confidence: 99%

Epithelial-Mesenchymal Transition is Superior to Vessels-Encapsulate Tumor Cluster in Promoting Metastasis of Hepatocellular Carcinoma: a Morphological Evidence

He¹,

Zhou²,

Jiang³

et al. 2017

J. Cancer

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Purpose Vessels-encapsulate tumor cluster (VETC) is a vascular pattern distinct from classical capillary-like pattern. It is reported that VETC structure is common in hepatocellular carcinoma (HCC) and can promote HCC metastasis in an epithelial-mesenchymal transition (EMT)-independent but VETC-dependent manner. However, the main metastatic manner of HCC containing both VETC and classical vascular structure (we called VETC±) is unknown.Methods Vascular pattern types and E-cadherin expression were evaluated by immunohistochemical staining in 168 HCC tissues, 50 pairs of primary HCC tissues and intrahepatic metastatic lesions, as well as 12 pairs of primary HCC tissues and major portal vein tumor thrombus. Survival and recurrence rates were evaluated using Kaplan-Meier analysis. The multivariate Cox proportional hazards model was used to determine the independent prognostic factors of HCC.Results VETC± cases were more common than VETC+ cases (HCC tissues with a VETC pattern fully distributed in the HCC section) in HCC. Statistical analysis showed that VETC± was an independent predictor of survival and recurrence. Furthermore, E-cadherin was positively correlated with the presence of VETC structure. In the case of HCCs with VETC±, their metastases (both intrahepatic and major vascular) were more likely to be VETC negative.Conclusions Our findings suggest that EMT may be superior to VETC in promoting HCC metastasis. Thus, both anti-EMT and anti-VETC agents should be considered in the case of HCC with VETC±.

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Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

Cited by 66 publications

References 61 publications

Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex

Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex

Genetic alterations in hepatocellular carcinoma: An update

Epithelial-Mesenchymal Transition is Superior to Vessels-Encapsulate Tumor Cluster in Promoting Metastasis of Hepatocellular Carcinoma: a Morphological Evidence

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