Overexpression of Romo1 is an unfavorable prognostic biomarker and a predictor of lymphatic metastasis in non-small cell lung cancer patients

Abstract

IntroductionReactive oxygen species modulator-1 (Romo1) is a protein that modulates levels of reactive oxygen species (ROS) and has been reported to affect cancer cell invasion and proliferation via persistent inflammation. Several studies have demonstrated the clinical application of Romo1 as a prognostic marker in non-small cell lung cancer (NSCLC); however, there have been no studies investigating the mechanism by which Romo1 adversely affects the prognosis of these patients.MethodsWe examined Romo1, ROS, and vascular endothelial growth factor (VEGF) in tumor tissues immunohistochemically. We conducted survival analyses of patients who had curative resection (n=30) in accordance with clinical parameters including levels of Romo1 expression.ResultsRomo1 levels were associated with serologic inflammatory markers and high lymphatic metastatic tendencies. Significantly longer disease-free survival (68.7 vs 24.2 months, P=0.031) and overall survival (92.7 vs 51.6 months) were observed in the group with low Romo1 compared with high Romo1. Survival outcomes were also significantly associated with serologic inflammatory markers. Spearman’s correlation analyses demonstrated significant positive correlations of Romo1 expression with VEGF-C (P=0.008, R=0.478) and ROS (P=0.016, R=0.436) in tumor samples.ConclusionThe current study demonstrates that Romo1 induces lymphatic metastasis of NSCLC by modulating persistent inflammation and oxidative stress (ROS)/VEGF signaling. Lymphatic metastasis associated with elevated Romo1 was shown to be a key reason for unfavorable survival rates.

<p>Reactive Oxygen Species Modulator 1 As An Adverse Prognostic Marker In Stage III Non-Small Cell Lung Cancer Treated With Radiotherapy: A Retrospective Pilot Study</p>

“…A very recent study showed that ROMO1 forms a viroporin-like nonselective cation channel that is inhibited by Fe 2+ ions, a transition ion involved in ROS metabolism 24. Clinical studies have consistently suggested that this channel protein is associated with early recurrence and worse survival of surgically-treated human malignancies including lung cancer 10,11,13,25. Moreover, it has been reported that ROMO1 overexpression is associated with treatment response and survival in NSCLC patients who were treated with platinum-based chemotherapy 12.…”

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“…ROMO1 gene encodes a mitochondrial membrane protein that has the effect on increasing intracellular reactive oxygen species [26]. Recent studies have shown that the ROMO1 gene product are highly expressed in cancer cells and triggers sustained inflammatory response [27]. In addition, PTNR22 are associated with immune diseases [28,29].…”

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“…MUS81 knockdown enhances sensitivity of colon cancer lines to cisplatin and other chemotherapy agents by activating the CHK1 pathway [181]. MGR2/ROMO1 is involved in protein import into the mitochondrial matrix and overexpression of ROMO1 has been associated with poor prognosis in colorectal [182] and non-small cell lung cancer patients [183]. MAK3/NAA30 , a component of the NatC complex ( Fig 8A ), induces p53-dependent apoptosis when knocked down in cancer cell lines [184].…”