LASP1 Is a HIF1α Target Gene Critical for Metastasis of Pancreatic Cancer

Zhao, Tiansuo; Ren, He; Li, Jing; Chen, Jing; Zhang, Huan; Wen, Xin; Sun, Yan; Sun, Lei; Yang, Yanling; Sun, Junwei; Wang, Xiuchao; Gao, Song; Huang, Chongbiao; Zhang, Huafeng; Yang, Shung‐Haur; Hao, Jihui

doi:10.1158/0008-5472.can-14-2040

Cited by 94 publications

(89 citation statements)

References 36 publications

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“…The final score was obtained by multiplying the intensity scores with staining range, and the results ranged from 0 to 9. For the final scores (intensity score Â percentage score), scores less than 2 were considered as negative staining, 2-3 indicated weak staining, 4-6 was moderate staining, and >6 was strong staining (18). For the in vivo angiogenesis experiments, staining with CD34 was quantified on the basis of the intensity of microvessel staining in selected fields.…”

Section: Immunohistochemistrymentioning

confidence: 99%

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Gao

et al. 2017

Cancer Research

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The transcription factor KLF6 has an essential role in the development and metastasis of multiple human cancers. Paradoxically, KLF6 expression was found to be attenuated in primary metastatic clear cell renal cell carcinoma (ccRCC), such that it is unclear how KLF6 affects malignant progression in this setting. In this study, we demonstrate that KLF6 attenuation in renal cells is sufficient to promote E2F1-mediated epithelialmesenchymal transition and metastatic prowess. In a mouse xenograft model of human ccRCC, silencing KLF6 increased tumor cell proliferation and malignant character, whereas E2F1 silencing reversed these properties. These effects were corroborated in a metastatic model system, where we observed a greater number of pulmonary metastatic lesions formed by ccRCC cells where KLF6 was silenced and E2F1 enforced. Analysis of clinical specimens of ccRCC revealed that low levels of KLF6 and high levels of E2F1 correlated closely with ccRCC development. Overall, our results established the significance of activating the KLF6-E2F1 axis in aggressive ccRCC, defining a novel critical signaling mechanism that drives human ccRCC invasion and metastasis. Cancer Res; 77(2); 330-42. Ó2016 AACR.

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Section: Immunohistochemistrymentioning

confidence: 99%

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Gao

et al. 2017

Cancer Research

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“…LASP1 mRNA expression was a significant negative predictor of overall survival. LASP1 has been shown to promote invasion and metastasis; particularly, LASP1 overexpression in pancreatic ductal adenocarcinomas was found to be significantly associated with lymph node metastasis and poor overall survival [43]. Therefore, it is plausible that tumor-associated elevations in LASP1 may contribute to LVI, which could explain why we no longer observed a significant hazard ratio when a LASP1 cutoff of 2.1 was used and instead only LVI was found to be a significant predictor of overall survival.…”

Section: Discussionmentioning

confidence: 99%

Proteomic profiling of lung adenocarcinoma indicates heightened DNA repair, antioxidant mechanisms and identifies LASP1 as a potential negative predictor of survival

et al. 2016

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BackgroundLung cancer is the leading cause of cancer mortality in the United States. Non-small cell lung cancer accounts for 85% of all lung cancers for which adenocarcinoma is the most common histological type. Management of lung cancer is hindered by high false-positive rates due to difficulty resolving between benign and malignant tumors. Better molecular analysis comparing malignant and non-malignant tissues will provide important evidence of the underlying biology contributing to tumorigenesis.MethodsWe utilized a proteomics approach to analyze 38 malignant and non-malignant paired tissue samples obtained from current or former smokers with early stage (Stage IA/IB) lung adenocarcinoma. Statistical mixed effects modeling and orthogonal partial least squares discriminant analysis were used to identify key cancer-associated perturbations in the adenocarcinoma proteome. Identified proteins were subsequently assessed against clinicopathological variables.ResultsTop cancer-associated protein alterations were characterized by: (1) elevations in APEX1, HYOU1 and PDIA4, indicative of increased DNA repair machinery and heightened anti-oxidant defense mechanisms; (2) increased LRPPRC, STOML2, COPG1 and EPRS, suggesting altered tumor metabolism and inflammation; (3) reductions in SPTB, SPTA1 and ANK1 implying dysregulation of membrane integrity; and (4) decreased SLCA41 suggesting altered pH regulation. Increased protein levels of HYOU1, EPRS and LASP1 in NSCLC adenocarcinoma was independently validated by tissue microarray immunohistochemistry. Immunohistochemistry for HYOU1 and EPRS indicated AUCs of 0.952 and 0.841, respectively, for classifying tissue as malignant. Increased LASP1 correlated with poor overall survival (HR 3.66 per unit increase; CI 1.37–9.78; p = 0.01).ConclusionThese results reveal distinct proteomic changes associated with early stage lung adenocarcinoma that may be useful prognostic indicators and therapeutic targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12014-016-9132-y) contains supplementary material, which is available to authorized users.

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“…Hypoxia contributes to disease progression and promotes tumor growth and invasion, and clinical studies have shown that high levels of hypoxia directly correlate with a poor prognosis in pancreatic cancer (7). The observed correlation between tumor hypoxia and patient prognosis is ascribed to therapeutic failure and hypoxiainduced pro-metastatic potential, as several studies have shown that hypoxia stimulates a more invasive, metastatic phenotype via multiple mechanisms (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

Zhou

Guo

Chen

et al. 2018

Molecular Cancer Research

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Hypoxia contributes to pancreatic cancer progression and promotes its growth and invasion. Previous research principally focused on hypoxia-inducible factor-1 alpha (HIF-1a) and HIF2a (HIF1A and EPAS1) as the major hypoxia-associated transcription factors in pancreatic cancer. However, the role of HIF-3a (HIF3A) has not been investigated. Therefore, HIF-1a, HIF-2a, and HIF-3a expression levels were measured under normoxic and hypoxic conditions. In addition, HIF-3a expression was measured in human pancreatic cancer tissue specimens and the impact of altered HIF-3a expression on cell invasion and migration was investigated in vitro and in vivo, as well as the underlying mechanisms. Under hypoxic conditions, HIF-3a expression was stimulated in pancreatic cancer cells to a greater degree than HIF-1a and HIF-2a expression. HIF-3a protein levels were also elevated in pancreatic cancer tissues and correlated with reduced survival and greater local invasion and distant metastasis, whereas knockdown of HIF-3a, under hypoxic conditions, suppressed pancreatic cancer cell invasion and migration. Under normoxia, HIF-3a overexpression promoted pancreatic cancer cell invasion and migration and stimulated F-actin polymerization. In summary, HIF-3a promotes pancreatic cancer cell invasion and metastasis in vivo and promotes pancreatic cancer cell invasion and metastasis by transcriptionally activating the RhoC-ROCK1 signaling pathway.Implications: HIF3a is overexpressed in pancreatic cancer, and targeting the HIF3a/RhoC-ROCK1 signaling pathway may be a novel therapeutic approach for the treatment of pancreatic cancer invasion and metastasis.

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LASP1 Is a HIF1α Target Gene Critical for Metastasis of Pancreatic Cancer

Cited by 94 publications

References 36 publications

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Proteomic profiling of lung adenocarcinoma indicates heightened DNA repair, antioxidant mechanisms and identifies LASP1 as a potential negative predictor of survival

HIF-3α Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC–ROCK1 Signaling Pathway

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