NBEAL2 encodes a BEACH-domain containing proteins with a crucial role in granule ontogeny of platelets[9, 10, 13]. NBEAL2 encoding protein is expected to have close relationship with CHS1, DLL1 and JAG1, known to play role in hematopoiesis. Mutation of NBEAL2 is a source of a series of disorders of granule ontogeny such as GPS, a severe and inherited bleeding disorders due to the lack of α-granules and their contents. Various NBEAL2 gene defects reported so far cause macrothrombocytopenia and synthetic disorder of α-granules[14]. However, a previous study demonstrated that deficiency in NBEAL2 and α-granules is capable of affecting the metastasis of melanoma cancer, which is more than their primary function in hemostasis[15]. Vladimir et al. discovered that NBEAL2 was one of biomarkers to detect ovarian cancer with ideal sensitivity and specificity[16]. Previous studies with administration of NBEAL2 knockout mouse demonstrated the failure of α-granules formation in megakaryocytes and platelets. Studies with NBEAL2 knockout mouse highlight emphasized the role of α-granules in promoting immune response, intervention of tissue repair and facilitating malignancy metastasis[17–19]. However, the role of NBEAL2 in malignancy remains unclear and further investigations are required. In this study,we sought to find the evidences that NBEAL2 have a tight relation with LIHC. In addition, potential signaling pathways involved to NBEAL2 in LIHC were explored to further understand the possible mechanism related to the regulation of LIHC progression by NBEAL2.
NBEAL2 expression is proved to play a critical role in LIHC progression in our study, especially as a biomarkers for prognosis in LIHC. The original gene Expression data downloaded from the TCGA database was analyzed and the experssion level of NBEAL2 in LIHC and adjacent nontumor tissues was compared. A remarkably higher expression level of NBEAL2 in LIHC compared with adjacent nontumor tissues was observed, which suggested that NBEAL2 was involved in the development of LIHC. The expression levels of NBEAL2 in groups classified by T stage and pathological stage were also detected. NBEAL2 exhibited no significant expression differences between groups classified according to pathological stage and T stage. Considering the close correlation between the expression level of NBEAL2 and survival, these data indicated that NBEAL2 may affect overall survival as a specific and independent impact factor.
Kaplan–Meier survival analysis gave the result that a lower expression of NBEAL2 was accompanied by a worse prognosis. The results of univariate analysis indicated that low NBEAL2 expression was associated with poorer overall survival while pathological stage and T stage were also related with the prognosis of patients with LIHC. Multivariate analysis suggested that the NBEAL2 expression is an independent predictor of the overall survival of LIHC patients. The data set forth in our study supported the potential of NBEAL2 as a biomarker for LIHC. Due to the lack of research on NBEAL2 in malignant tumors, the significance of NBEAL2 in other malignancy remains obscure. Interestingly, a recent study pointed out that high NBALE2 expression level may be a risk factor for poor survival of patients with IDH1 wild-type Glioblastoma(GBM), which seems contrary with our results[20]. Another research get similar conclusion with us that low NBALE2 expression level was correlated with poorer overall survival of HNSCC patients[12]. we postulated that NBEAL2 has dissimilar roles in malignancy as it can be a tumor suppressor gene or an oncogene.
To explore the potential molecular mechanism of NBEAL2 in LIHC, GSEA was used to analyze the expression profile data of LIHC tumor tissues grouped by different NBEAL2 expression levels. It was found that adherens junction, chronic myeloid leukemia, endocytosis, FC gamma R (FCGR)-mediated phagocytosis, GNRH signaling pathway, inositol phosphate metabolism, notch signaling pathway, pancreatic cancer, and pathways in cancer were significantly correlated with high NBEAL2 expression LIHC. Since adherens junctions is continuously crucial for maintaining epithelial form and function, and the dysregulation of this pathway damage the integrity of endothelial barrier thus promoting various cancer metastasis[21–23]. Endocytosis is an energy-consumpted process, in which cells internalize surrounding substances in the form of vesicles. The inbalance of endocytosis pathways plays an important role in the proliferation, migration, and treatment of cancer cells[24–27]. Fc gamma receptor (FCGR)-mediated phagocytosis is an indispensable part of cellular immunity including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis activate innate immunity[28, 29]. Since ADCC and phagocytosis participate in tumor cell killing, we speculate that polymorphisms in FCGR-related genes were related with the progression of malignancy. Gonadotropin-releasing hormone (GnRH) is believed to have a tight association with non-small cell lung carcinoma (NSCLC)[30, 31], but the relation between GnRH and LIHC remains unclear. Inositol phosphate metabolism pathway affect cell differentiation, migration and regulate phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway[32]. Deregulation of inositol phosphate metabolism are correlated with various types of cancer including hepatocellular cancers, prostate, brain, breast cancers[33–35]. The Notch signaling pathway is evolutionarily conserved and involved in cell proliferation, differentiation and apoptosis throughout the life cycle. Previous research comfirmed the positive effect of notch signaling pathway in the amplification of cancer stem cells, which promoting the formation, proliferation and recurrence of the cancer[36–38].
Drug metabolism cytochrome P450, fatty acid metabolism, glycine-serine and threonine metabolism, metabolism of xenobiotics by cytochrome P450, peroxisome, PPAR signaling pathway, primary bile acid biosynthesis, retinol metabolism, and tryptophan metabolism were remarkably associated with low NBEAL2 expression LIHC. The suppression of cytochrome P450 (CYP)-mediated drug clearance is observed in the status of systemic infammation and immunity therapy for cancer[39–41]. The change of CYP enzyme activity may cause either rapidly removal or accumulation of anti-cancer drugs. Reprogramming of fatty acid metabolism has been regarded as a hallmark of cancer, and a recent study pointed out that fatty acid-binding protein 5 (FABP5) upregulation due to the dysregulation of fatty acid metabolism may drive LIHC progression[42, 43]. Accumulating evidence highlighted that hyperactivation of the serine and glycine biosynthetic pathway facilitate the formation of tumor[44, 45]. Suppression of xenobiotics metabolism by cytochrome P450 due to either polymorphisms in genes or acquired reason is considered as a risk factor of various malignant tumors[46, 47]. Peroxisome proliferator-activated receptors(PPARs) plays an important role in carcinogenesis and various metabolic disorders[48]. Previous research indicated that alteration of retinol metabolism is significantly correlated with prostate and breast cancer risk[49, 50]. Tryptophan metabolism plays essential roles in both immunity disorder and cancer formation. Recent research supported that tryptophan metabolism could be a poential therapeutic target in cancer[51, 52].
The limitation of our research is the incomplete of clinical information, including lack of tumor size, surgical treatment and surgical details. Finally, the lack of laboratory data makes our research results unconvincing.
In conclusion, the data set forth in our study supported that the expression level of NBEAL2 in LIHC tissues was higher than that in adjacent tissues. On the contrary, lower expression of NBEAL2 in LIHC tissues was correlated with shorter OS. Importantly, univariate and multivariate analyses identified reduced NBEAL2 expression in LIHC as an independent risk factor for shorter OS. Due to the lack of laboratory data, whether it could be a marker for the diagnosis and the prognosis
of LIHC remains obscure.