Proangiogenic factor midkine is increased in melanoma patients with sleep apnea and induces tumor cell proliferation

Cubillos‐Zapata, Carolina; Martínez‐García, Miguel Ángel; Díaz‐García, Elena; Toledano, Víctor; Campos‐Rodríguez, Francisco; Sánchez‐de‐la‐Torre, Manuel; Nagore, Eduardo; Martorell-Calatayud, A.; Blasco, Luis; Pastor, Esther; Abad‐Capa, Jorge; Montserrat, Josep M.; Cabriada-Nuño, Valentin; Cano‐Pumarega, Irene; Corral‐Peñafiel, Jaime; Arias, Eva; Mediano, Olga; Somoza‐González, María; Dalmau‐Arias, Joan; Almendros, Isaac; Farré, Ramón; López‐Collazo, Eduardo; Gozal, David; García‐Río, Francisco

doi:10.1096/fj.202001247rr

Cited by 13 publications

(12 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In this situation, together with the IH-induced, HIF1α dependent, overexpression of the programmed death-1/programmed death-ligand 1 immune checkpoint [5], the limited ability to block cells that arise with neoplastic transformation could explain the higher incidence of tumors. Moreover, OSA causes a modulation of the microenvironment that favors cancer progression through the persistence of immunosuppression and the induction of various proangiogenic factors, such as vascular endothelial growth factor [7] and midkine [36]. However, the TGFβ induction mediated by PSPC1 suggests that OSA could also affect the intrinsic properties of eventual tumor cells promoting their aggressiveness.…”

Section: Discussionmentioning

confidence: 99%

Intermittent Hypoxia Mediates Paraspeckle Protein-1 Upregulation in Sleep Apnea

Díaz‐García

García-Tovar

Casitas

et al. 2021

Cancers

View full text Add to dashboard Cite

As some evidence suggests that hypoxia might be an inducer of nuclear paraspeckle formation, we explore whether intermittent hypoxia (IH)-mediated paraspeckle protein-1 (PSPC1) overexpression might contribute to the activation of tumor growth factor (TGF)β-SMAD pathway in patients with obstructive sleep apnea (OSA). This activation would promote changes in intracellular signaling that would explain the increased cancer aggressiveness reported in these patients. Here, we show that patients with OSA exhibit elevated PSPC1 levels both in plasma and in monocytes. Our data suggest that PSPC1 is ultimately delivered to the plasma through its cleavage from OSA monocytes by matrix metalloproteinase-2 (MMP2). In addition, IH promotes PSPC1, TGFβ, and MMP2 expression in monocytes through the hypoxia-inducible factor. Lastly, both PSPC1 and TGFβ induce increased expression of genes that drive the epithelial-to-mesenchymal transition. Our study details the mechanism by which hypoxemia upmodulates the extracellular release of PSPC1 by means of MMP2, such that plasma PSPC1 together with TGFβ activation signaling further promotes tumor metastasis and supports cancer aggressiveness in patients with OSA.

show abstract

Section: Discussionmentioning

confidence: 99%

Intermittent Hypoxia Mediates Paraspeckle Protein-1 Upregulation in Sleep Apnea

Díaz‐García

García-Tovar

Casitas

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…MDK has been reported to promote cancer EMT via TGF-β, WNT and Notch 2 signalings ( 25 ). Additionally, MDK has also been implicated in promoting cancer proliferation ( 27 ), angiogenesis ( 28 ), stemness ( 29 ), drug resistance ( 30 ), immunosuppression ( 31 ), and resistance to immune checkpoint blockade ( 31 ), closely correlated with advanced cancer progression and poor survival ( 27 , 32 , 33 ).…”

Section: Discussionmentioning

confidence: 99%

Targeting MDK Abrogates IFN-γ-Elicited Metastasis inCancers of Various Origins

Zheng

Li²,

Li³

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

IFN-γ is a pleiotropic cytokine with immunomodulatory and tumoricidal functions. It has been used as an anti-tumor agent in adjuvant therapies for various cancers. Paradoxically, recent advances have also demonstrated pro-tumorigenic effects of IFN-γ, especially in promoting cancer metastasis, with the mechanism remains unclear. This will undoubtedly hinder the application of IFN-γ in cancer treatment. Here, we verified that IFN-γ treatment led to activation of the epithelial-to-mesenchymal transition (EMT) programme and metastasis in cell lines of various cancers, including the kidney cancer cell line Caki-1, the lung cancer cell line A549, the cervical carcinoma cell line CaSki, the breast cancer cell line BT549 and the colon cancer cell line HCT116. We further disclosed that midkine (MDK), an emerging oncoprotein and EMT inducer, is a common responsive target of IFN-γ in these cell lines. Mechanistically, IFN-γ upregulated MDK via STAT1, a principle downstream effector in the IFN-γ signalling. MDK is elevated in the majority of cancer types in the TCGA database, and its overexpression drove EMT activation and cancer metastasis in all examined cell lines. Targeting MDK using a specific MDK inhibitor (iMDK) broadly reversed IFN-γ-activated EMT, and subsequently abrogated IFN-γ-triggered metastasis. Collectively, our data uncover a MDK-dependent EMT inducing mechanism underlying IFN-γ-driven metastasis across cancers which could be attenuated by pharmacological inhibition of MDK. Based on these findings, we propose that MDK may be used as a potential therapeutic target to eliminate IFN-γ-elicited pro-metastatic adverse effect, and that combined MDK utilization may expand the application of IFN-γ in cancer and improve the clinical benefits from IFN-γ-based therapies.

show abstract

“…Serum midkine (MDK), as a lymphangiogenesis-related biomarker, its overexpression has been identified in patients with NSCLC as a potential therapeutic target for its development, metastasis, and angiogenesis ( 82 , 83 ). Lymphangiogenesis, in addition to angiogenesis, mediates tumor vascularization, which meets the oxygen and nutrient requirements for tumor growth and metastasis ( 84 ). Recent studies have shown that individuals at high risk for lung cancer with moderate-to-severe OSA have elevated expression of MDK (non-OSA: 1536 pg/mL, 95% CI 840–2360 pg/mL; moderate-to-severe OSA: 5902 pg/mL, 95% CI 816–8337 pg/mL) ( 85 ).…”

Section: Pathogenesismentioning

confidence: 99%

A review of obstructive sleep apnea and lung cancer: epidemiology, pathogenesis, and therapeutic options

Yuan,

Hu,

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

Despite undeniable advances in modern medicine, lung cancer still has high morbidity and mortality rates. Lung cancer is preventable and treatable, and it is important to identify new risk factors for lung cancer, especially those that can be treated or reversed. Obstructive sleep apnea (OSA) is a very common sleep-breathing disorder that is grossly underestimated in clinical practice. It can cause, exacerbate, and worsen adverse outcomes, including death and various diseases, but its relationship with lung cancer is unclear. A possible causal relationship between OSA and the onset and progression of lung cancer has been established biologically. The pathophysiological processes associated with OSA, such as sleep fragmentation, intermittent hypoxia, and increased sympathetic nervous excitation, may affect normal neuroendocrine regulation, impair immune function (especially innate and cellular immunity), and ultimately contribute to the occurrence of lung cancer, accelerate progression, and induce treatment resistance. OSA may be a contributor to but a preventable cause of the progression of lung cancer. However, whether this effect exists independently of other risk factors is unclear. Therefore, by reviewing the literature on the epidemiology, pathogenesis, and treatment of lung cancer and OSA, we hope to understand the relationships between the two and promote the interdisciplinary exchange of ideas between basic medicine, clinical medicine, respiratory medicine, sleep medicine, and oncology.

show abstract

Proangiogenic factor midkine is increased in melanoma patients with sleep apnea and induces tumor cell proliferation

Cited by 13 publications

References 44 publications

Intermittent Hypoxia Mediates Paraspeckle Protein-1 Upregulation in Sleep Apnea

Intermittent Hypoxia Mediates Paraspeckle Protein-1 Upregulation in Sleep Apnea

Targeting MDK Abrogates IFN-γ-Elicited Metastasis inCancers of Various Origins

A review of obstructive sleep apnea and lung cancer: epidemiology, pathogenesis, and therapeutic options

Contact Info

Product

Resources

About