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The role of apoptosis defects in malignant mesothelioma pathogenesis with an impact on prognosis and treatment

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Abstract

Malignant mesothelioma (MM) is a highly aggressive tumor that is strongly related to asbestos fiber exposure. The tumorigenesis procedure in MM is complex, and many pathogenetic mechanisms including chronic inflammation, deregulation of cell death, and the genomic copy-number losses and gains may contribute to carcinogenesis. MM cells are resistant to TRAIL-mediated apoptosis due to defects in extrinsic apoptotic pathway. CAPS, a regulator of cell cycle and death, may contribute to the MM development as well. BAP1 is the most frequently inactivated gene in MPM; BAP1 deficiency triggers malignant transformation via disruption of DNA repair, transcription regulation, cell metabolism, apoptosis, and ferroptosis. In addition, bcl-2 family proteins as well as abnormal activation of PI3 K/Akt/mTOR pathway and deregulation of the Wnt signaling pathway may result in MM tumorigenesis. Finally, the Hippo pathway plays a critical role in MPM development. Mutations of NF2 and LATS lead to YAP activation in MPM. Thus, inhibition of YAP activity by YAP inhibitors could be a potentially promising treatment option for MM. In conclusion, extensive genetic alterations exist in mesotheliomas associated with the signaling of apoptotic HM cells death. The comprehension of these pathways may contribute to enhancing survival via developing new effective therapeutic strategies.

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Abbreviations

MM:

Malignant mesothelioma

HM:

Human mesothelial

HMGB1:

High-mobility group protein B1

MΦs:

Macrophages

IL:

Interleukin

BAL:

Bronchoalveolar lavage

S100-A9:

Calcium- and zinc-binding protein

HSP27:

Heat shock protein 27

MTAP:

Methylthioadenosine phosphorylase

MPM:

Malignant pleural mesothelioma

CFAP45:

Cilia- and flagella-associated protein 45

ULK2:

Unc-51-like kinase 2

RyR2:

Ryanodine receptor

FLIP:

FLICE-like inhibitory protein

ERK:

Extracellular-signal-regulated kinase

EGF:

Epidermal growth factor

CASP1:

Caspase 1

TRAF1:

TNF receptor-associated factor 1

SEMA3E:

Semaphorin 3E

RPS6KA2:

Ribosomal protein S6 kinase alpha-2

ARF:

ADP-ribosylation factor

mcl-1:

Myeloid cell leukemia 1

JNKs:

c-Jun N-terminal kinases

AVEN:

Apoptosis and Caspase Activation Inhibitor

APAF1:

Apoptotic protease activating factor 1

PI3-K:

Phosphatidylinositol-3-kinases

MTOR:

Mammalian target of rapamycin

S6K1:

Ribosomal protein S6 kinase beta-1

MapK:

Mitogen-activated protein kinase

WNT1:

Wnt family member 1

MYC:

MYC Proto-Oncogene

SAPK:

Stress-activated protein kinases

CCND1:

Cyclin D1

SFRP2/4:

Secreted Frizzled-Related Protein 2/4

DKK1:

Dickkopf-related protein 1

MDM2:

Mouse double minute 2 homolog

pRB:

Retinoblastoma protein

SLC7A11:

Solute Carrier Family 7 Member 11

IAP:

Inhibitors of apoptosis proteins

TRAF:

TNF receptor-associated factors

CARP-1:

Cell division cycle and apoptosis regulator protein 1

XAF1:

XIAP-associated factor 1

TROY:

Tumor necrosis factor receptor superfamily, member 19

BIRC5:

Baculoviral IAP Repeat Containing 5

YAP:

Yes-associated protein

ROCK2:

Rho-associated coiled-coil containing protein kinase 2

NF2:

Neurofibromin 2

LATS2:

Large tumor suppressor homolog 2

SAV1:

Salvador homolog 1

RASSF:

Ras-association domain family

TEAD1:

Transcriptional enhancer factor TEF-1

ROCK:

Rho-associated protein kinase

REN:

Neural progenitor cell line

PPIX:

Protoporphyrin IX

RAGE:

Receptor for advanced glycation endproducts

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Authors and Affiliations

  1. Department of Anatomy, Histology and Embryology, Medical School, University of Ioannina, 45110, Ioannina, Greece

    Vasiliki Galani & Yotanna Dalavanga

  2. Department of Internal Medicine, Ippokratio Hospital, Thessaloníki, Greece

    Anna Varouktsi

  3. 3rd Department of Internal Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

    Stamatis S. Papadatos

  4. Department of Forensic Pathology, Medical School, University of Ioannina, Ioannina, Greece

    Antigoni Mitselou

  5. Department of Cancer Biobank Center, University of Ioannina, Ioannina, Greece

    Ioannis Sainis

  6. Department of Pneumonology, University of Ioannina, Medical School, Ioannina, Greece

    Stavros Constantopoulos

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  1. Vasiliki Galani
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Galani, V., Varouktsi, A., Papadatos, S.S. et al. The role of apoptosis defects in malignant mesothelioma pathogenesis with an impact on prognosis and treatment. Cancer Chemother Pharmacol 84, 241–253 (2019). https://doi.org/10.1007/s00280-019-03878-3

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  • DOI: https://doi.org/10.1007/s00280-019-03878-3

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