Unconjugated Bilirubin Is a Novel Prognostic Biomarker for Nasopharyngeal Carcinoma and Inhibits Its Metastasis via Antioxidation Activity

Abstract

Distant metastasis is the most common cause of treatment failure and mortality in nasopharyngeal carcinoma (NPC) patients. Thus, it is important to understand the mechanism of NPC metastasis and identify reliable prognostic factors. In this study, we investigated the prognostic value of unconjugated bilirubin (UCB), which was previously considered a byproduct of heme catabolism, in NPC patients and examined the effects of UCB on NPC metastasis. The receiver operating characteristic analysis-generated UCB cutoff point for DMFS was 9.7 mmol/L. We found that higher UCB levels were significantly associated with favorable distant metastasis-free survival (DMFS, 93.3% vs. 84.2%, P < 0.001) in NPC patients and was an independent predictor for DMFS (HR, 0.416; 95% confidence interval, 0.280-0.618; P < 0.001). We next found that UCB treatment impaired the invasion capability of NPC cells and potently inhibited lung metastasis of NPC cells in nude mice. Further investigation showed that UCB inhibited reactive oxygen species production, which is involved in the repression of ERK1/2 activation and matrix metalloproteinase-2 (MMP-2) expression. Moreover, lower levels of ERK1/2 phosphorylation and MMP-2 expression were observed in the NPC lung metastases of nude mice administered UCB. Taken together, our results indicate that UCB is a significantly favorable factor for DMFS in NPC patients and may play an important role in NPC chemoprevention. Cancer Prev Res; 9(2);

The prognostic impact of serum bilirubin in stage IV colorectal cancer patients

“…At the same time, a previous study on nasopharyngeal carcinoma (NPC) showed that IBI could inhibit NPC metastasis by inhibiting reactive oxygen species (ROS) production, and acted as a favorable prognostic factor. 11 What's more, IBI was also reported to be an independent prognostic factor in NSCLC. 13 On the other hand, it was reported that IBI could induce cell apoptosis in colon cancer cell lines by triggering mitochondrial depolarization, 17 suggesting that elevated IBI level could predict good outcome.…”

“…16 However, these cut-off values varied from previous studies (date were listed in Table 3). [11][12][13][14][15] With the aspect to CRC, Gao used the threshold were slightly lower than our cut-off value of DBIL. Number of patients from different tumor stages and different geographic regions may be could explain this phenomenon.…”

“…4,[8][9][10] At same time, serum bilirubin was also widely investigated as a useful prognostic indicator for non-liver diseaserelated mortality in various cancers, including CRC. [11][12][13][14][15] However, as for Zhang's study, they only reported stage II-III CRC patients. 15…”

Bilirubin Attenuates ER Stress-Mediated Inflammation, Escalates Apoptosis and Reduces Proliferation in the LS174T Colonic Epithelial Cell Line

“…Induction of apoptosis via activation of caspases is a critical feature associated with the effectiveness of potential cancer treatments [42,43] including the use of tetrapyrrolic bile pigments in human cancer cells [44]. Apart from being used as a novel biomarker for nasopharyngeal carcinoma [45], UCB has the potential to cause cell cycle arrest at G0/G1 and exert pro-oxidant effects at high concentrations [46]. Human biliverdin reductase, which chemically reduces biliverdin to bilirubin, was recently implicated as a regulator in cancer development and maybe useful in designing biomarkers for cancer patients [47].…”

The prognostic value of serum bilirubin in colorectal cancer patients with surgical resection

“…18,19 However, upon consideration of the inconvenient and expensive detection of UGT1A1, it is speculated that serum bilirubin, which was tested routinely, might be an available prognostic biomarker for CRC. At the same time, serum bilirubin, including total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBI) have been reported by numerous studies as promising prognostic biomarkers in various cancers, including breast cancer, 20 non-small-cell lung cancer, 21 nasopharyngeal carcinoma, 22 pancreatic adenocarcinoma, and CRC. 23,24 Until now, few studies have reported the prognostic value of serum bilirubin in CRC.…”