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Open AccessArticle

Tumor Transcriptome Reveals High Expression of IL-8 in Non-Small Cell Lung Cancer Patients with Low Pectoralis Muscle Area and Reduced Survival

1
Department of Morphology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-689, São Paulo, Brazil
2
Department of Surgery and Orthopedics, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618687, São Paulo, Brazil
3
Experimental Research Unit, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618687, São Paulo, Brazil
4
Department of Clinical Genetics, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle 7100, Denmark
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(9), 1251; https://doi.org/10.3390/cancers11091251
Received: 26 June 2019 / Revised: 15 July 2019 / Accepted: 29 July 2019 / Published: 26 August 2019
(This article belongs to the Special Issue Cancer Cachexia)
Cachexia is a syndrome characterized by an ongoing loss of skeletal muscle mass associated with poor patient prognosis in non-small cell lung cancer (NSCLC). However, prognostic cachexia biomarkers in NSCLC are unknown. Here, we analyzed computed tomography (CT) images and tumor transcriptome data to identify potentially secreted cachexia biomarkers (PSCB) in NSCLC patients with low-muscularity. We integrated radiomics features (pectoralis muscle, sternum, and tenth thoracic (T10) vertebra) from CT of 89 NSCLC patients, which allowed us to identify an index for screening muscularity. Next, a tumor transcriptomic-based secretome analysis from these patients (discovery set) was evaluated to identify potential cachexia biomarkers in patients with low-muscularity. The prognostic value of these biomarkers for predicting recurrence and survival outcome was confirmed using expression data from eight lung cancer datasets (validation set). Finally, C2C12 myoblasts differentiated into myotubes were used to evaluate the ability of the selected biomarker, interleukin (IL)-8, in inducing muscle cell atrophy. We identified 75 over-expressed transcripts in patients with low-muscularity, which included IL-6, CSF3, and IL-8. Also, we identified NCAM1, CNTN1, SCG2, CADM1, IL-8, NPTX1, and APOD as PSCB in the tumor secretome. These PSCB were capable of distinguishing worse and better prognosis (recurrence and survival) in NSCLC patients. IL-8 was confirmed as a predictor of worse prognosis in all validation sets. In vitro assays revealed that IL-8 promoted C2C12 myotube atrophy. Tumors from low-muscularity patients presented a set of upregulated genes encoding for secreted proteins, including pro-inflammatory cytokines that predict worse overall survival in NSCLC. Among these upregulated genes, IL-8 expression in NSCLC tissues was associated with worse prognosis, and the recombinant IL-8 was capable of triggering atrophy in C2C12 myotubes. View Full-Text
Keywords: secretome; computed tomography; Interleukin-8; tumor-derived factor; C2C12 cells; cachexia secretome; computed tomography; Interleukin-8; tumor-derived factor; C2C12 cells; cachexia
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Santiloni Cury, S.; de Moraes, D.; Paccielli Freire, P.; de Oliveira, G.; Venâncio Pereira Marques, D.; Javier Fernandez, G.; Dal-Pai-Silva, M.; Nishida Hasimoto, É.; Pintor dos Reis, P.; Regina Rogatto, S.; Francisco Carvalho, R. Tumor Transcriptome Reveals High Expression of IL-8 in Non-Small Cell Lung Cancer Patients with Low Pectoralis Muscle Area and Reduced Survival. Cancers 2019, 11, 1251.

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