Abstract
CISD2 is a redox-sensitive gene critical for normal development and mitochondrial integrity. CISD2 was known to have aberrant expression in several types of human cancers. However, its relation with lung cancer is still not clear. In this study we found CISD2 mRNA was significantly upregulated in lung adenocarcinoma (ADC) samples, compared with their adjacent normal counterparts, and was correlated with tumor stage, grade, and prognosis based on analysis of clinical specimens-derived expression data in public domain and our validation assay. Cell based assay indicated that CISD2 expression regulated accumulation of reactive oxygen species (ROS), polarization of mitochondrial membrane potential, as well as cell viability, apoptosis, invasiveness, and tumorigenicity. In addition, CISD2 expression was found significantly correlated with stress response/redox signaling genes such as EGR1 and GPX3, while such correlations were also found valid in many public domain data. Taken together, upregulation of CISD2 is involved in an increased antioxidant capacity in response to elevated ROS levels during the formation and progression of lung ADC. The molecular mechanism underlying how CISD2 regulates ROS homeostasis and augments malignancy of lung cancer warrants further investigations.
Highlights
Lung cancers are a major cause of cancer-related deaths globally, mostly attributable to late diagnosis and lack of efficient treatment[1]
In this study, using a combined approach relating evidence from analysis of public gene expression data derived from clinical specimens of lung cancer tissues, cell-based assays, and animal xenograft models, we have identified the oncogenic properties of CISD2 and its clinical significance in lung ADC
We propose a model of CISD2–reactive oxygen species (ROS)–EGR1/GPX3 axis signaling (Fig. 7), in which increased levels of CISD2 contribute to the neutralization of excessive ROS production, which would otherwise increase antitumor activity mediated at least by the tumor suppressors EGR1 and GPX3
Summary
Lung cancers are a major cause of cancer-related deaths globally, mostly attributable to late diagnosis and lack of efficient treatment[1]. ROS are known to play a pivotal role in carcinogenesis by promoting proliferation, invasiveness, and metastasis, and by inhibiting apoptosis. CISD2 activity is critically required for normal development, overexpression of CISD2 has been linked to several human cancers, including breast cancer[13,14], cervical cancer[15], gastric cancer[16], and laryngeal squamous carcinoma (SQC)[17], indicating it plays an oncogenic role. Despite these findings, it is still unclear whether CISD2 is associated with lung cancer. The antioxidant but oncogenic roles of CISD2 in lung cancer are discussed
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