Original ArticleThe oncoprotein HBXIP up-regulates YAP through activation of transcription factor c-Myb to promote growth of liver cancer
Introduction
The dysregulation of Hippo pathway is wildly involved in the tumorigenesis [1], [2], [3], [4], in which Yes-associated protein (YAP) is able to induce the expression of pro-proliferative and anti-apoptotic genes as a transcription co-activator in the complex of TEAD family [5], [6], [7]. CTGF, CYR61 and SOX2 serve as the downstream target genes of YAP [8], [9]. A host of factors including cell density, extracellular matrix stiffness, G protein–coupled receptors and leukemia inhibitory factor receptor can influence YAP activity through modulating the Hippo pathway. The heightened expression or genomic amplification of YAP is frequently observed in many cancers [10], [11], [12], [13], [14], [15]. The highly expressed YAP is involved in multiple process of liver disease including liver repair, regeneration, hepatocellular carcinoma (HCC) [16], [17], [18]. YAP can serve as an independent prognostic marker in HCC [19]. However, the mechanism of YAP regulation in liver cancer is poorly understood.
Hepatitis B X-interacting protein (HBXIP), originally identified for interacting with hepatitis B virus X proteins, is a conserved ∼18 kDa protein among mammalian species [20]. HBXIP acts as an oncoprotein in controlling cell proliferation, apoptosis and division [21], [22], [23], [24]. HBXIP as a regulator component participates in amino acids-mediated mTORC1 activation [25]. Our group manifested that HBXIP could import into the nucleus of breast cancer cells, acting as a transcription co-activator of transcription factors such as Sp1, cAMP-response element binding protein (CREB), c-Myc and E2F1, to accelerate the progression of liver and breast cancer [26], [27], [28], [29], [30]. However, whether HBXIP is involved in the regulation of YAP in cancers is not well documented.
The transcription factor c-Myb is encoded by the MYB proto-oncogene [31], [32]. Overexpression of c-Myb contributes to malignant transformation by regulating genes participating in multiple processes of tumourigenesis, such as cell growth, angiogenesis and resistance to apoptosis [33], [34], [35], [36]. Myb is able to affect tumor cell self-renewal through the Wnt signaling pathway [37]. Recent studies have shown that c-Myb plays an important role in the development of gastric cancer (GC) [38]. The target genes of c-Myb include SOX2, Bcl-2, Bax, c-Myc, and etc [39]. However, the role of c-Myb in the regulation of YAP remains unclear.
In this study, we investigated the role of oncoprotein HBXIP in modulation of YAP in liver cancer. Interestingly, we found that HBXIP was able to up-regulate YAP through activating YAP promoter, involving co-activating c-Myb, to accelerate the growth of hepatoma cells. Our finding provides new insights into the mechanism by which HBXIP regulates YAP expression in the development of liver cancer.
Section snippets
Patient samples
Twenty-six hepatocellular carcinoma (HCC) tissue samples and their corresponding non-tumorous liver tissues were obtained from Tianjin First Center Hospital and Tianjin Tumor Hospital (Tianjin, China) after surgical resection. Written consents approving the use of tissue samples for research purposes were obtained from HCC patients. The study protocol was approved by the Institute Research Ethics Committee at Nankai University. The information of HCC patients was shown in Supplementary Table S1.
The expression of HBXIP is positively associated with that of YAP in clinical HCC tissues
Our laboratory has reported that the oncoprotein HBXIP contributes to the progression of cancer through acting as a co-activator of transcription factors [26], [27], [28], [29], [30]. Lots of studies have proven that the highly expressed YAP plays a crucial role in the development of cancer [10], [11], [12], [13], [14], [15]. Accordingly, we supposed that HBXIP might be involved in the regulation of Hippo-YAP signaling. Immunohistochemistry (IHC) staining analysis exhibited that the positive
Discussion
Hippo signaling plays pivotal roles in cell proliferation and organ size, and mounting studies have reported that this pathway is involved in the development of numerous cancers [1], [2], [3], [4], [45]. Our laboratory has reported that HBXIP, as an oncoprotein and a transcription co-activator, contributes to the development of breast cancer and liver cancer [26], [27], [28], [29], [30]. However, the effect of HBXIP on YAP in hepatocarcinogenesis is poorly understood. In this study, we
Acknowledgements
This work was supported by the grants of the National Basic Research Program of China (973 Program, No. 2015CB553905, 2015CB553703), the National Natural Scientific Foundation of China (Nos. 81372186, 81272218, 31470756, 31670771, 31670769), and Tianjin Natural Scientific Foundation (No. 14JCZDJC32800).
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2020, Life SciencesCitation Excerpt :For example, HBXIP promotes cell proliferation through NF-kB signaling pathway [7]; HBXIP activates mTORC1 signaling pathway through amino acids to promote cancer cell proliferation and migration [8]; HBXIP promotes human breast cancer growth through pAKT/MDM2 pathway [9]. Many studies show that HBXIP is closely related to the occurrence and development of many malignant tumors, including breast cancer [10], liver cancer [11], lung cancer [12], etc., which may be involved as an oncoprotein in the proliferation, apoptosis, and migration of various tumor cells. However, the expression and the clinicopathological significance of HBXIP in CRC have not been reported.
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The authors contribute equally to the work.