Translational Activation of HIF1α by YB-1 Promotes Sarcoma Metastasis

El-Naggar, Amal M.; Veinotte, Chansey J.; Cheng, Hongwei; Grünewald, Thomas G.P.; Negri, Gian Luca; Somasekharan, Syam Prakash; Corkery, Dale; Tirode, Franck; Mathers, Joan; Khan, Debjit; Kyle, Alastair H.; Baker, Jennifer H.E.; LePard, Nancy E.; McKinney, Steven; Hajee, Shamil; Bosiljcic, Momir; Leprivier, Gabriel; Tognon, Cristina E.; Minchinton, Andrew I.; Bennewith, Kevin L.; Delattre, Olivier; Wang, Yuzhuo; Dellaire, Graham; Berman, Jason N.; Sorensen, Poul H.

doi:10.1016/j.ccell.2015.04.003

Cited by 225 publications

(203 citation statements)

References 46 publications

Supporting

Mentioning

192

Contrasting

Order By: Relevance

“…Overall, these results demonstrate that the 3D hypoxic hydrogel regulates sarcoma matrix remodeling through hypoxic induction of HIF-1α expression. These results are consistent with various sarcoma studies in vivo (15,24,25), suggesting that the HI hydrogels are an appropriate 3D model with the necessary biological attributes to study sarcoma cell invasion and migration.…”

Section: Resultssupporting

confidence: 88%

Intratumoral oxygen gradients mediate sarcoma cell invasion

Lewis

Park

Tang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

114

View full text Add to dashboard Cite

Hypoxia is a critical factor in the progression and metastasis of many cancers, including soft tissue sarcomas. Frequently, oxygen (O 2 ) gradients develop in tumors as they grow beyond their vascular supply, leading to heterogeneous areas of O 2 depletion. Here, we report the impact of hypoxic O 2 gradients on sarcoma cell invasion and migration. O 2 gradient measurements showed that large sarcoma mouse tumors (>300 mm 3 ) contain a severely hypoxic core [≤0.1% partial pressure of O 2 (pO 2 )] whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1-6% pO 2 ). To analyze tumor invasion, we used O 2 -controllable hydrogels to recreate the physiopathological O 2 levels in vitro. Small tumor grafts encapsulated in the hydrogels revealed increased invasion that was both faster and extended over a longer distance in the hypoxic hydrogels compared with nonhypoxic hydrogels. To model the effect of the O 2 gradient accurately, we examined individual sarcoma cells embedded in the O 2 -controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through hypoxia-inducible factor-1α (HIF-1α) activation. We further found that in the hypoxic gradient, individual cells migrate more quickly, across longer distances, and in the direction of increasing O 2 tension. Treatment with minoxidil, an inhibitor of hypoxia-induced sarcoma metastasis, abrogated cell migration and matrix remodeling in the hypoxic gradient. Overall, we show that O 2 acts as a 3D physicotactic agent during sarcoma tumor invasion and propose the O 2 -controllable hydrogels as a predictive system to study early stages of the metastatic process and therapeutic targets.hydrogel | sarcoma | hypoxia | gradients | migration S oft tissue sarcomas are a heterogeneous group of malignant cancers derived from transformed cells of mesenchymal origin (1, 2). Approximately 13,000 new cases per year are diagnosed in the United States alone, with 25-50% of patients developing recurrent and metastatic disease (3-5). Current clinical data suggest that undifferentiated pleomorphic sarcoma (UPS) is one of the most aggressive sarcoma subtypes, which frequently results in lethal pulmonary metastases that are insensitive to radio/chemotherapy. It has recently become apparent that sarcoma progression and metastasis are regulated by microenvironmental cues, such as extracellular matrix (ECM) remodeling, stiffness modulation, cellto-cell/matrix interactions, signaling factors, and spatial gradients (6-8). Of all these factors, low intratumoral oxygen (O 2 ; hypoxia) is most dramatically associated with pulmonary metastasis and poor clinical outcomes (9, 10).Intratumoral hypoxia occurs when the partial pressure of O 2 (pO 2 ) falls below 5%, and it is a commonly observed feature of many sarcomas. Regional hypoxia develops as rapidly growing tumors outstrip their blood supply and as a consequence of aberrant tumor angiogenesis. As a result, O 2 gradients develop throughout the growing tumor. Tumor hypoxia promotes c...

show abstract

Section: Resultssupporting

confidence: 88%

Intratumoral oxygen gradients mediate sarcoma cell invasion

Lewis

Park

Tang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

114

View full text Add to dashboard Cite

show abstract

“…Hence, long-term expression of YB-1 might terminate the MyoDmediated differentiation of myocytes after forming myotubes in ischemic limbs. Recently, the YB-1 was reported to directly regulate hypoxia-inducible factor (HIF) 1α, a critical transcription factor that regulates adaptive responses to hypoxia and plays a pivotal role in wound healing (El-Naggar et al 2015;Xu et al 2017). Although the association between YB-1 and HIF1α was not investigated in the present study, it is possible that the increased expression of YB-1 after ischemic injury could enhance wound healing via increased expression of HIF1α.…”

Section: Discussionmentioning

confidence: 73%

Increased Expression of Y-Box-Binding Protein-1 in Hind-Limb Muscles During Regeneration from Ischemic Injury in Mice

Fuke

Narita

Wada

et al. 2018

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

Critical limb ischemia (CLI) is the most severe complication of peripheral arterial disease (PAD). Understanding the molecular mechanisms underlying tissue repair after CLI is necessary for preventing PAD progression. Y-box binding protein-1 (YB-1) regulates the expression of many genes in response to environmental stresses. We aimed to determine whether YB-1 is involved in ischemic muscle regeneration. A mouse ischemic hind-limb model was generated; namely, the femoral, saphenous, and popliteal arteries in the left hind limb were ligated. The right hind limb, with skin incisions alone, served as control. Hind limbs (n = 3-5 for each time point) were examined on day 0 (before the operation) and on postoperative days 1, 2, 7, 10, and 14, and the biceps femoris, adductor, rectus femoris, and gracilis muscles were subjected to histopathological and immunohistochemical analyses. In ischemic limbs, myogenesis, triggered by an increase in myotubes, began on day 7; thereafter, regenerated muscles gradually increased in volume. RT-PCR analysis showed that YB-1 mRNA levels were increased in the limbs after ischemic injury, peaked on day 2, and subsequently decreased. On day 7, expression levels of MyoD and alphasmooth muscle actin (αSMA) mRNAs were significantly higher in ischemic muscles than in control muscles. Immunohistochemical analysis revealed increased YB-1 immunoreactivity in myoblasts and myotubes on day 7, which was decreased by day 14. The immunoreactive αSMA and smooth muscle myosin heavy chain were transiently increased in myotubes. This is the first report showing the increased expression of YB-1 during muscle regeneration after ischemic injury.

show abstract

“…YBX1 functions as both a DNA and RNA binding protein and has been implicated in numerous cellular processes, including regulation of transcription and translation, premRNA splicing, DNA reparation, and mRNA packaging (36). YBX1 activation has been associated with cancer progression (37,38), the epithelial-mesenchymal transition (39), metastasis (40), and drug resistance (41,42). Western blot with a specific antibody confirmed that YBX1 is enriched in the TP53TG1 pull-down (Fig.…”

Section: Tp53tg1 Binds To the Rna Binding Protein Ybx1 And Prevents Itsmentioning

confidence: 94%

Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer

Díaz‐Lagares

Crujeiras

López-Serra

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

136

128

View full text Add to dashboard Cite

Long noncoding RNAs (lncRNAs) are important regulators of cellular homeostasis. However, their contribution to the cancer phenotype still needs to be established. Herein, we have identified a p53-induced lncRNA, TP53TG1, that undergoes cancer-specific promoter hypermethylation-associated silencing. In vitro and in vivo assays identify a tumor-suppressor activity for TP53TG1 and a role in the p53 response to DNA damage. Importantly, we show that TP53TG1 binds to the multifaceted DNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. TP53TG1 epigenetic inactivation in cancer cells releases the transcriptional repression of YBX1-targeted growth-promoting genes and creates a chemoresistant tumor. TP53TG1 hypermethylation in primary tumors is shown to be associated with poor outcome. The epigenetic loss of TP53TG1 therefore represents an altered event in an lncRNA that is linked to classical tumoral pathways, such as p53 signaling, but is also connected to regulatory networks of the cancer cell.DNA methylation | long noncoding RNA | epigenetics | cancer

show abstract

Translational Activation of HIF1α by YB-1 Promotes Sarcoma Metastasis

Cited by 225 publications

References 46 publications

Intratumoral oxygen gradients mediate sarcoma cell invasion

Intratumoral oxygen gradients mediate sarcoma cell invasion

Increased Expression of Y-Box-Binding Protein-1 in Hind-Limb Muscles During Regeneration from Ischemic Injury in Mice

Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer

Contact Info

Product

Resources

About