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

Author(s):Show less -

Cury, Sarah Santiloni ^[1] ; de Moraes, Diogo ^[1] ; Freire, Paula Paccielli ^[1] ; de Oliveira, Grasieli ^[1] ; Pereira Marques, Douglas Venancio ^[1] ; Fernandez, Geysson Javier ^[1] ; Dal-Pai-Silva, Maeli ^[1] ; Hasimoto, Erica Nishida ^[2] ; dos Reis, Patricia Pintor ^{[2, 3]} ; Rogatto, Silvia Regina ^[4] ; Carvalho, Robson Francisco ^[1]

Affiliation

^[1] Sao Paulo State Univ UNESP, Inst Biosci, Dept Morphol, BR-18618689 Botucatu, SP - Brazil

^[2] Sao Paulo State Univ UNESP, Fac Med, Dept Surg & Orthoped, BR-18618687 Botucatu, SP - Brazil

^[3] Sao Paulo State Univ UNESP, Fac Med, Expt Res Unit, BR-18618687 Botucatu, SP - Brazil

^[4] Univ Southern Denmark, Vejle Hosp, Inst Reg Hlth Res, Dept Clin Genet, DK-7100 Vejle - Denmark

• Document type: Journal article
• Source: CANCERS; v. 11, n. 9 SEP 2019.
• Web of Science Citations: 1

Abstract

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. (AU)

• FAPESP's process: 17/21223-9 - Identification of potential secretome biomarkers in non-small-cell lung cancer cachexia
• Grantee: Sarah Santiloni Cury
• Support Opportunities: Scholarships in Brazil - Master