The Association of IFI27 Expression and Fatigue Intensification during Localized Radiation Therapy: Implication of a Para-Inflammatory Bystander Response

Abstract

The mechanisms behind fatigue intensification during cancer therapy remain elusive. The interferon alpha-inducible protein 27 (IFI27) was the most up-regulated gene based on our previous microarray data in fatigued men with non-metastatic prostate cancer receiving localized external beam radiation therapy (EBRT). The purpose of this study was to confirm the IFI27 up-regulation and determine its association with fatigue intensification during EBRT. Peripheral blood samples and fatigue scores were collected at three time points—prior to EBRT, at midpoint, and at completion of EBRT. Confirmatory quantitative real time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) were utilized to verify the microarray results. Subjects were a total of 40 Caucasian men with prostate cancer; 20 scheduled for EBRT (65.6 ± 7.5 years old), and 20 on active surveillance as controls (62.8 ± 6.1 years old). Significant IFI27 expression overtime during EBRT was confirmed by qPCR (p < 0.5), which correlated with fatigue scores during EBRT (R = −0.90, p = 0.006). Alterations in mechanisms associated with immune response and mitochondrial function that explain the up-regulation of IFI27 may provide an understanding of the pathways related to the intensification of fatigue during localized radiation therapy.

Genomic Profile of Fatigued Men Receiving Localized Radiation Therapy

“…The trajectory of fatigue that we reported in this study is consistent with the findings of other studies (Langston et al, 2013;Miaskowski et al, 2008) and our previous findings (Hsiao et al, 2014(Hsiao et al, , 2012Saligan et al, 2013). These findings suggest that biologic mechanisms related to the repeated stress imposed by daily doses of irradiation are likely involved in the worsening of fatigue symptoms in this population.…”

“…In a previous study, we noted that SNCA was upregulated in fatigued men during EBRT (Saligan et al, 2013). CA1 belongs to the zinc metalloenzyme family, and functions by catalyzing the reversible hydration of carbon dioxide and participates in a variety of biological processes such as maintenance of acid-base balance, bone resorption, and calcification (Sly & Hu, 1995).…”

“…The normalization of raw signal intensity values, transformation of quantile normalization value, detection of outliers, and statistical methods were performed according to the procedures prescribed previously (Saligan et al, 2013;X. M. Wang et al, 2007).…”

The Etiology and management of radiotherapy-induced fatigue

“…These biomarkers and biological pathways include alpha-synuclein [34], neurotrophic factors ( BDNF, GDNF , and SNAPIN ) [35], para-inflammatory bystander markers (the interferon alpha-inducible protein 27, IFI27 ) [36], and immunespecific response markers (e.g. MS4A1 ) [37], mitochondrial associated genes ( BCL2L1, FIS2, BCS1L , and SCL25A37 ) as well as RIF-associated biological pathways (glutathione biosynthesis, γ-glutamyl cycle, and antigen presentation pathways) [37].…”

Understanding cancer-related fatigue: advancing the science

“…While the potential for involvement of these diverse mechanisms has been demonstrated, no biomarker has been consistently associated with CRF in large sample studies [5,6,10,14,15]. Furthermore, although a large variety of questionnaires to evaluate CRF have been developed, there is little consensus about what outcomes define this condition, hampering comparisons between trials [3].…”