Homeobox containing 1 inhibits liver cancer progression by promoting autophagy as well as inhibiting stemness and immune escape

Zhao,Hengli; Jia,Huifeng; Han,Qiuju; Zhang,Jian

doi:10.3892/or.2018.6551

Homeobox containing 1 inhibits liver cancer progression by promoting autophagy as well as inhibiting stemness and immune escape

Authors:
- Hengli Zhao
- Huifeng Jia
- Qiuju Han
- Jian Zhang
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Affiliations: Institute of Immunopharmaceutical Sciences, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, P.R. China
Published online on: July 10, 2018 https://doi.org/10.3892/or.2018.6551
Pages: 1657-1665

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Abstract

Homeobox containing 1 (HMBOX1) is a novel transcription repressor that is significantly downregulated in human liver cancer tissues and cell lines, but the exact biological function of HMBOX1 in liver cancer is still unknown. We observed a negative association between HMBOX1 expression level and the clinical stages of liver cancer. HMBOX1 also increased the LC3 II/LC3 I ratio, the endogenous autophagy marker, and inhibited the p38/AKT/mTOR pathway. Furthermore, cancer stem cell specific genes, including CD133, KLF4, ESG1 and SOX2, were significantly downregulated upon HMBOX1 overexpression. Finally, the susceptibility of HepG2 cells to NK cell‑mediated cytolysis was increased by HMBOX1 overexpression and weakened by siRNA‑mediated inhibition of HMBOX1. All these findings indicated that HMBOX1 expression in hepatocytes could protect against the progression of liver cancer, and the underlying mechanisms may include promoting autophagy, inhibiting CSC phenotype and increasing the sensitivity of tumor cells to NK cell cytolysis. Therefore, HMBOX1 may be useful for developing new treatments for liver cancer.

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1	Schütte K, Bornschein J and Malfertheiner P: Hepatocellular carcinoma-epidemiological trends and risk factors. Dig Dis. 27:80–92. 2009. View Article : Google Scholar
2	Lv B, Zhang L, Miao R, Xiang X, Dong S, Lin T, Li K and Kai Q: Comprehensive analysis and experimental verification of LINC01314 as a tumor suppressor in hepatoblastoma. Biomed Pharmacother. 98:783–792. 2018. View Article : Google Scholar : PubMed/NCBI
3	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
4	Marin JJG, Briz O, Herraez E, Lozano E, Asensio M, Di Giacomo S, Romero MR, Osorio-Padilla LM, Santos-Llamas AI, Serrano MA, et al: Molecular bases of the poor response of liver cancer to chemotherapy. Clin Res Hepatol Gastroenterol. 42:182–192. 2018. View Article : Google Scholar : PubMed/NCBI
5	Cheng Z, Li X and Ding J: Characteristics of liver cancer stem cells and clinical correlations. Cancer Lett. 379:230–238. 2016. View Article : Google Scholar : PubMed/NCBI
6	Llovet JM and Bruix J: Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology. 37:429–442. 2003. View Article : Google Scholar : PubMed/NCBI
7	Chen S, Saiyin H, Zeng X, Xi J, Liu X, Li X and Yu L: Isolation and functional analysis of human HMBOX1, a homeobox containing protein with transcriptional repressor activity. Cytogenet Genome Res. 114:131–136. 2006. View Article : Google Scholar : PubMed/NCBI
8	Dai J, Wu L, Zhang C, Zheng X, Tian Z and Zhang J: Recombinant expression of a novel human transcriptional repressor HMBOX1 and preparation of anti-HMBOX1 monoclonal antibody. Cell Mol Immunol. 6:261–268. 2009. View Article : Google Scholar : PubMed/NCBI
9	Holland PW, Booth HA and Bruford EA: Classification and nomenclature of all human homeobox genes. BMC Biol. 5:472007. View Article : Google Scholar : PubMed/NCBI
10	Su L, Zhao H, Sun C, Zhao B, Zhao J, Zhang S, Su H and Miao J: The role of Hmbox1 in endothelial differentiation of bone-marrow stromal cells by a small molecule. ACS Chem Biol. 5:1035–1043. 2010. View Article : Google Scholar : PubMed/NCBI
11	Ma H, Su L, Yue H, Yin X, Zhao J, Zhang S, Kung H, Xu Z and Miao J: HMBOX1 interacts with MT2A to regulate autophagy and apoptosis in vascular endothelial cells. Sci Rep. 12:151212015. View Article : Google Scholar
12	Feng X, Luo Z, Jiang S, Li F, Han X, Hu Y, Wang D, Zhao Y, Ma W, Liu D, et al: The telomere-associated homeobox-containing protein TAH1/HMBOX1 participates in telomere maintenance in ALT cells. J Cell Sci. 126:3982–3989. 2013. View Article : Google Scholar : PubMed/NCBI
13	Wu L, Zhang C, Zheng X, Tian Z and Zhang J: HMBOX1, homeobox transcription factor, negatively regulates interferon-γ production in natural killer cells. Int Immunopharmacol. 11:1895–1900. 2011. View Article : Google Scholar : PubMed/NCBI
14	Wu L, Zhang C and Zhang J: HMBOX1 negatively regulates NK cell functions by suppressing the NKG2D/DAP10 signaling pathway. Cell Mol Immunol. 8:433–440. 2011. View Article : Google Scholar : PubMed/NCBI
15	Dai J, Zhang C, Tian Z and Zhang J: Expression profile of HMBOX1, a novel transcription factor, in human cancers using highly specific monoclonal antibodies. Exp Ther Med. 2:487–490. 2011. View Article : Google Scholar : PubMed/NCBI
16	López-Terrada D, Cheung SW, Finegold MJ and Knowles BB: Hep G2 is a hepatoblastoma-derived cell line. Hum Pathol. 40:1512–1515. 2009. View Article : Google Scholar
17	Hou L, Li Y, Song H, Zhang Z, Sun Y, Zhang X and Wu K: Protective macroautophagy is involved in vitamin E succinate effects on human gastric carcinoma cell line SGC-7901 by inhibiting mTOR axis phosphorylation. PLoS One. 10:e01328292015. View Article : Google Scholar : PubMed/NCBI
18	Zhang C, Jia X, Wang K, Bao J, Li P, Chen M, Wan JB, Su H, Mei Z and He C: Polyphyllin VII induces an autophagic cell death by activation of the JNK pathway and inhibition of PI3K/AKT/mTOR pathway in HepG2 cells. PLoS One. 11:e01474052016. View Article : Google Scholar : PubMed/NCBI
19	Ghoshal S, Fuchs BC and Tanabe KK: STAT3 is a key transcriptional regulator of cancer stem cell marker CD133 in HCC. Hepatobiliary Surg Nutr. 5:201–203. 2016. View Article : Google Scholar : PubMed/NCBI
20	Bahnassy AA, Fawzy M, El-Wakil M, Zekri AR, Abdel-Sayed A and Sheta M: Aberrant expression of cancer stem cell markers (CD44, CD90, and CD133) contributes to disease progression and reduced survival in hepatoblastoma patients: 4-year survival data. Transl Res. 165:396–406. 2015. View Article : Google Scholar : PubMed/NCBI
21	Singh U, Quintanilla RH, Grecian S, Gee KR, Rao MS and Lakshmipathy U: Novel live alkaline phosphatase substrate for identification of pluripotent stem cells. Stem Cell Rev. 8:1021–1029. 2012. View Article : Google Scholar : PubMed/NCBI
22	Li Y, Li A, Glas M, Lal B, Ying M, Sang Y, Xia S, Trageser D, Guerrero-Cázares H, Eberhart CG, et al: c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc Nat Acad Sci USA. 108:9951–9956. 2011. View Article : Google Scholar : PubMed/NCBI
23	Noguchi K, Eguchi H, Konno M, Kawamoto K, Nishida N, Koseki J, Wada H, Marubashi S, Nagano H, Doki Y, et al: Susceptibility of pancreatic cancer stem cells to reprogramming. Cancer Sci. 106:1182–1187. 2015. View Article : Google Scholar : PubMed/NCBI
24	Kawasaki A, Shinkai Y, Yagita H and Okumura K: Expression of perforin in murine natural killer cells and cytotoxic T lymphocytes in vivo. Eur J Immunol. 22:1215–1219. 1992. View Article : Google Scholar : PubMed/NCBI
25	Subleski JJ, Hall VL, Back TC, Ortaldo JR and Wiltrout RH: Enhanced antitumor response by divergent modulation of natural killer and natural killer T cells in the liver. Cancer Res. 66:11005–11012. 2006. View Article : Google Scholar : PubMed/NCBI
26	Bai X, Wang S, Tomiyama-Miyaji C, Shen J, Taniguchi T, Izumi N, Li C, Bakir HY, Nagura T, Takahashi S, et al: Transient appearance of hepatic natural killer cells with high cytotoxicity and unique phenotype in very young mice. Scand J Immunol. 63:275–281. 2006. View Article : Google Scholar : PubMed/NCBI
27	Yang Y, Han Q, Hou Z, Zhang C, Tian Z and Zhang J: Exosomes mediate hepatitis B virus (HBV) transmission and NK-cell dysfunction. Cell Mol Immunol. 14:465–475. 2017. View Article : Google Scholar : PubMed/NCBI
28	Xu D, Han Q, Hou Z, Zhang C and Zhang J: miR-146a negatively regulates NK cell functions via STAT1 signaling. Cell Mol Immunol. 14:712–720. 2017. View Article : Google Scholar : PubMed/NCBI
29	Ishiyama K, Ohdan H, Ohira M, Mitsuta H, Arihiro K and Asahara T: Difference in cytotoxicity against hepatocellular carcinoma between liver periphery natural killer cells in humans. Hepatology. 43:362–372. 2006. View Article : Google Scholar : PubMed/NCBI
30	Sung MW, Johnson JT, Van Dongen G and Whiteside TL: Protective effects of interferon-gamma on squamous-cell carcinoma of head and neck targets in antibody-dependent cellular cytotoxicity mediated by human natural killer cells. Int J Cancer. 66:393–399. 1996. View Article : Google Scholar : PubMed/NCBI
31	Rautou PE, Mansouri A, Lebrec D, Durand F, Valla D and Moreau R: Autophagy in liver diseases. J Hepatol. 53:1123–1134. 2010. View Article : Google Scholar : PubMed/NCBI
32	Czaja MJ: Functions of autophagy in hepatic and pancreatic physiology and disease. Gastroenterology. 140:1895–1908. 2011. View Article : Google Scholar : PubMed/NCBI
33	Kwanten WJ, Martinet W, Michielsen PP and Francque SM: Role of autophagy in the pathophysiology of nonalcoholic fatty liver disease: A controversial issue. World J Gastroenterol. 20:7325–7338. 2014. View Article : Google Scholar : PubMed/NCBI
34	Sun K, Guo XL, Zhao QD, Jing YY, Kou XR, Xie XQ, Zhou Y, Cai N, Gao L, Zhao X, et al: Paradoxical role of autophagy in the dysplastic and tumor-forming stages of hepatocarcinoma development in rats. Cell Death Dis. 4:e5012013. View Article : Google Scholar : PubMed/NCBI
35	Zhou R, Yazdi AS, Menu P and Tschopp J: A role for mitochondria in NLRP3 inflammasome activation. Nature. 469:221–225. 2011. View Article : Google Scholar : PubMed/NCBI
36	Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, et al: Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 12:222–230. 2011. View Article : Google Scholar : PubMed/NCBI
37	Castillo EF, Dekonenko A, Arko-Mensah J, Mandell MA, Dupont N, Jiang S, Delgado-Vargas M, Timmins GS, Bhattacharya D, Yang H, et al: Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. Proc Nat Acad Sci USA. 109:E3168–E3176. 2012. View Article : Google Scholar : PubMed/NCBI
38	Jordan CT, Guzman ML and Noble M: Cancer stem cells. N Engl J Med. 355:1253–1261. 2006. View Article : Google Scholar : PubMed/NCBI
39	Magee JA, Piskounova E and Morrison SJ: Cancer stem cells: Impact, heterogeneity, and uncertainty. Cancer Cell. 21:283–296. 2012. View Article : Google Scholar : PubMed/NCBI
40	Ma S: Biology and clinical implications of CD133⁺ liver cancer stem cells. Exp Cell Res. 319:126–132. 2013. View Article : Google Scholar : PubMed/NCBI
41	Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, Zheng BJ and Guan XY: Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology. 132:2542–2556. 2007. View Article : Google Scholar : PubMed/NCBI
42	Rountree CB, Senadheera S, Mato JM, Crooks GM and Lu SC: Expansion of liver cancer stem cells during aging in methionine adenosyltransferase 1A-deficientmice. Hepatology. 47:1288–1297. 2008. View Article : Google Scholar : PubMed/NCBI
43	Sui Q, Zhang J, Sun X, Zhang C, Han Q and Tian Z: NK cells are the crucial antitumor mediators when STAT3-mediated immunosuppression is blocked in hepatocellular carcinoma. J Immunol. 193:2016–2023. 2014. View Article : Google Scholar : PubMed/NCBI