Calpain‐2 triggers prostate cancer metastasis via enhancing CRMP4 promoter methylation through NF‐κB/DNMT1 signaling pathway

Gao, Xin; Mao, Yunfei; Xiao, Chutian; Li, Ké; Liu, Wei; Li, Liaoyuan; Pang, Jun

doi:10.1002/pros.23512

Cited by 16 publications

(12 citation statements)

References 32 publications

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“…The finding that NRP2 regulates Bmi‐1 and modulates IGF‐1R signaling in PCa underscores its importance in PCa and as possible marker for treatment response for drugs targeting the IGF‐1R pathway . Moreover, calpain‐mediated promoter methylation of the antimetastatic collapsing response mediator protein‐4 (CRMP4) also promotes PCa metastases through the VEGFC/NRP2 axis . Furthermore, it has already been shown that immunohistochemical staining of NRP1, the other member of the neuropilin family, in PCa tissues was associated with increased tumor stage and Gleason grading as well as with nodal status …”

Section: Discussionmentioning

confidence: 97%

“…13 Moreover, calpain-mediated promoter methylation of the antimetastatic collapsing response mediator protein-4 (CRMP4) also promotes PCa metastases through the VEGFC/NRP2 axis. 29 Furthermore, it has already been shown that immunohistochemical staining of NRP1, the other member of the neuropilin family, in PCa tissues was associated with increased tumor stage and Gleason grading as well as with nodal status. 14 Accordingly, we evaluated the role of immunohistochemical staining of NRP2 and VEGFC as ligand of NRP2 on a TMA as potential prognostic markers for PCa patients treated by RP.…”

Section: Discussionmentioning

confidence: 99%

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Neuropilin‐2 is an independent prognostic factor for shorter cancer‐specific survival in patients with acinar adenocarcinoma of the prostate

Borkowetz

Froehner

Rauner

et al. 2019

Intl Journal of Cancer

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Neuropilin‐2 (NRP2) is a member of the neuropilin receptor family and known to regulate autophagy and mTORC2 signaling in prostate cancer (PCa). Our study investigated the association of immunohistochemical NRP2 expression with clinicopathological data in PCa patients. For this purpose, we generated a tissue microarray with prostate tissue specimens from 400 PCa patients treated by radical prostatectomy. We focused on patients with high‐risk factors such as extraprostatic extension (pT ≥ 3), Gleason score ≥8 and/or the presence of regional lymph node metastases (pN1). Protein levels of NRP2, the vascular endothelial growth factor C (VEGFC) and oncogenic v‐ets avian erythroblastosis virus E26 oncogene homolog (ERG) gene as an indicator for TMPRSS2‐ERG fusion was assessed in relation to the patients' outcome. NRP2 emerged as an independent prognostic factor for cancer‐specific survival (CSS) (hazard ratio 2.360, 95% confidence interval = 1.2–4.8; p = 0.016). Moreover, the association between NRP2 expression and shorter CSS was also especially pronounced in patients at high risk for progression (log‐rank test: p = 0.010). We evaluated the association between NRP2 and the TMPRSS2‐ERG gene fusion status assessed by immunohistochemical nuclear ERG staining. However, ERG staining alone did not show any prognostic significance. NRP2 immunostaining is significantly associated with shorter CSS in ERG‐negative tumors (log‐rank test: p = 0.012). No prognostic impact of NRP2 expression on CSS was observed in ERG‐positive tumors (log‐rank test: p = 0.153). Our study identifies NRP2 as an important prognostic marker for a worse clinical outcome especially in patients with a high‐risk PCa and in patients with ERG‐negative PCa.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Neuropilin‐2 is an independent prognostic factor for shorter cancer‐specific survival in patients with acinar adenocarcinoma of the prostate

Borkowetz

Froehner

Rauner

et al. 2019

Intl Journal of Cancer

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“…38,39 Calpain-2 expression and activity are elevated throughout the metastatic cascade, including the primary tumor, lymph node metastases, and distant metastases of epithelial cancers such as colorectal cancer, squamous cell carcinoma, and breast cancer. [40][41][42][43][44][45][46][47] We therefore explored the role of calpain as a putative regulator of integrin shutdown. Calpain-2 protein expression was mildly increased in hypoxic and DMOG-treated 2D culture compared with control conditions (Fig.…”

Section: Elevated Calpain-2 Function Mediates Blebbing-amoeboid Migramentioning

confidence: 99%

“…Calpain is activated in both early invasive primary tumors and metastatic lesions and further has been implicated in predicting poor prognosis in clinical epithelial cancers. [40][41][42][43]47 To explore whether calpain is activated in the invasion zone of epithelial tumors in vivo, we applied the calpain sensor CMAC to fresh-frozen sections of human HN-31 and Detroit562 HN-SCC after 6 to 8 weeks of orthotopic growth in nude mice. The invasion pattern of both tumors comprised multicellular nests and groups, typical for cross-sectioned collective invasion strands ( Fig.…”

Section: Calpain Activity Amoeboid Conversion and Relevance For Metamentioning

confidence: 99%

Calpain-2 regulates hypoxia/HIF-induced amoeboid reprogramming and metastasis

Boekhorst

Jiang

Mählen

et al. 2020

Preprint

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Hypoxia, through hypoxia inducible factor (HIF), drives cancer cell invasion and metastatic progression in various cancer types, leading to poor prognosis. In epithelial cancer, hypoxia further induces the transition to amoeboid cancer cell dissemination, yet the molecular mechanisms, relevance for metastasis, and effective interventions to combat hypoxia-induced amoeboid reprogramming remain unclear. Here, we identify calpain-2 as key regulator and anti-metastasis target of hypoxia-induced transition from collective to amoeboid dissemination of breast and head and neck (HN) carcinoma cells. Hypoxia-induced amoeboid dissemination occurred through low ECM-adhesive, bleb-based amoeboid movement, which effectively invaded into 3D collagen with low-oxidative and -glycolytic energy metabolism, revealing an microenvironmentally-induced, energy-conserving dissemination route in epithelial cancers. Hypoxia-induced calpain-2 mediated amoeboid conversion by deactivating beta1 integrins, through enzymatic cleavage of the focal adhesion adaptor protein talin-1.Consequently, targeted downregulation of calpain-2 or pharmacological intervention restored talin-1 integrity, beta1 integrin engagement and reverted blebbing-amoeboid to elongated phenotypes under hypoxia. Calpain-2 activity was required for hypoxia-induced blebbing-amoeboid conversion in the orthotopic mouse dermis, and upregulated in invasive HN tumor xenografts in vivo, and attenuation of calpain activity prevented hypoxia-induced metastasis to the lungs. This identifies the calpain-2/talin-1/beta1 integrin axis as mechanosignaling program and promising intervention target of plasticity of cancer cell invasion and metastasis formation in epithelial cancers under hypoxia. IntroductionCancer cell invasion initiates a multistep cascade to metastasis, which converts local neoplasia into a life-threatening systemic disease. 1-3 Invading cancer cells migrate away from the primary tumor and penetrate blood and lymph vessels, followed by systemic spreading and metastatic colonization of distant organs. 1,3 For tissue invasion, cancer cells deploy a range of collective and individual cell 3 migration strategies. Collective invasion of multicellular groups occurs when cells are held together by cell-cell adhesion, whereas single-cell migration lacks cell-cell cohesion and connectivity. 4 Mesenchymal single-cell migration depends on effective integrin-mediated adhesion to the extracellular matrix (ECM), which supports spindle-like cell elongation and directs matrix metalloproteases (MMPs) for ECM remodeling and path generation. 5 Amoeboid movement of roundish or ellipsoid cells engages only weak adhesion to the ECM, lacks ECM remodeling and, instead deploys kinetic deformation of the cell body for passage through 3D tissue. 6 Besides the cell shape and the strength of ECM interactions, protrusion types differ between amoeboid migration modes. Amoeboid-moving leukocytes and cancer cells develop actin-rich pseudopodia and filopodia at the leading edge, which generate protrusive...

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“…CRMP4a is the shorter splicing variant compared with CRMP4b and has been identified as a tumor metastasis suppressor in prostate cancers 8 . Proteomic and genomic analyses revealed that CRMP4a expression was significantly reduced in metastatic tumor tissues mainly due to promoter methylation [22][23][24] . CRMP4 expression could be enhanced at the transcriptional level by Figure 6.…”

Section: Discussionmentioning

confidence: 99%

CRMP4a suppresses cell motility by sequestering RhoA activity in prostate cancer cells

Xiao

et al. 2018

Cancer Biology & Therapy

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Calpain‐2 triggers prostate cancer metastasis via enhancing CRMP4 promoter methylation through NF‐κB/DNMT1 signaling pathway

Abstract: Calpain-2 may contribute to the promoter methylation of CRMP4 to repress its transcription, leading to the metastasis of PCa via enhancing VEGFC expression.

Cited by 16 publications

References 32 publications

Neuropilin‐2 is an independent prognostic factor for shorter cancer‐specific survival in patients with acinar adenocarcinoma of the prostate

Neuropilin‐2 is an independent prognostic factor for shorter cancer‐specific survival in patients with acinar adenocarcinoma of the prostate

Calpain-2 regulates hypoxia/HIF-induced amoeboid reprogramming and metastasis

CRMP4a suppresses cell motility by sequestering RhoA activity in prostate cancer cells

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