Heme oxygenase-1 retards hepatocellular carcinoma progression through the microRNA pathway

Zou,Chaoxia; Zou,Chendan; Cheng,Wanpeng; Li,Qiang; Han,Zhongjing; Wang,Xiaona; Jin,Jianfeng; Zou,Jiaqi; Liu,Zhiyan; Zhou,Zhongqiu; Zhao,Weiming; Du,Zhimin

doi:10.3892/or.2016.5056

Heme oxygenase-1 retards hepatocellular carcinoma progression through the microRNA pathway

Authors:
- Chaoxia Zou
- Chendan Zou
- Wanpeng Cheng
- Qiang Li
- Zhongjing Han
- Xiaona Wang
- Jianfeng Jin
- Jiaqi Zou
- Zhiyan Liu
- Zhongqiu Zhou
- Weiming Zhao
- Zhimin Du
View Affiliations

Affiliations: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, Heilongjiang, P.R. China, Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China, Department of Hemopathology, General Hospital of Daqing Oil Field, Daqing, Heilongjiang, P.R. China, Institute of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China
Published online on: August 30, 2016 https://doi.org/10.3892/or.2016.5056
Pages: 2715-2722

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Heme metabolism system is involved in microRNA (miRNA) biogenesis. The complicated interplay between heme oxygenase-1 (HO-1) and miRNA has been observed in various tissues and diseases, including human malignancy. In the present study, our data showed that stable HO-1 overexpression in hepatocellular carcinoma (HCC) cells downregulated several oncomiRs. The most stably downregulated are miR-30d and miR-107. Iron, one of HO-1 catalytic products, was an important mediator in this regulation. Cell function analysis demonstrated that HO-1 inhibited the proliferation and metastasis of HepG2 cells, whereas miR-30d/miR-107 improved the proliferative and migratory ability of HepG2 cells. The beneficial effect of HO-1 in HCC inhibition could be reversed by upregulating miR-30d and miR-107. Akt and ERK pathways may be involved in the regulation of HO-1/miR-30d/miR-107 in HCC. These data indicate that HO-1 significantly suppresses HCC progression by regulating the miR-30d/miR-107 level, suggesting miR-30d/miR-107 regulation as a new molecular mechanism of HO-1 anticancer effect.

View Figures

View References

1	Maines MD, Trakshel GM and Kutty RK: Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible. J Biol Chem. 261:411–419. 1986.PubMed/NCBI
2	Jozkowicz A, Was H and Dulak J: Heme oxygenase-1 in tumors: Is it a false friend? Antioxid Redox Signal. 9:2099–2117. 2007. View Article : Google Scholar : PubMed/NCBI
3	Zou C, Zhang H, Li Q, Xiao H, Yu L, Ke S, Zhou L, Liu W, Wang W, Huang H, et al: Heme oxygenase-1: A molecular brake on hepatocellular carcinoma cell migration. Carcinogenesis. 32:1840–1848. 2011. View Article : Google Scholar : PubMed/NCBI
4	Deininger MH, Meyermann R, Trautmann K, Duffner F, Grote EH, Wickboldt J and Schluesener HJ: Heme oxygenase (HO)-1 expressing macrophages/microglial cells accumulate during oligodendroglioma progression. Brain Res. 882:1–8. 2000. View Article : Google Scholar : PubMed/NCBI
5	Doi K, Akaike T, Fujii S, Tanaka S, Ikebe N, Beppu T, Shibahara S, Ogawa M and Maeda H: Induction of haem oxygenase-1 nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth. Br J Cancer. 80:1945–1954. 1999. View Article : Google Scholar : PubMed/NCBI
6	De Palma G, Mozzoni P, Acampa O, Internullo E, Carbognani P, Rusca M, Goldoni M, Corradi M, Tiseo M, Apostoli P, et al: Expression levels of some antioxidant and epidermal growth factor receptor genes in patients with early-stage non-small cell lung cancer. J Nucleic Acids. 2010:pii: 147528. 2010. View Article : Google Scholar : PubMed/NCBI
7	Lee SE, Yang H, Jeong SI, Jin YH, Park CS and Park YS: Induction of heme oxygenase-1 inhibits cell death in crotonaldehyde-stimulated HepG2 cells via the PKC-δ-p38-Nrf2 pathway. PLoS One. 7:e416762012. View Article : Google Scholar
8	Kim DH, Kim JH, Kim EH, Na HK, Cha YN, Chung JH and Surh YJ: 15-Deoxy-Delta12,14-prostaglandin J2 upregulates the expression of heme oxygenase-1 and subsequently matrix metalloproteinase-1 in human breast cancer cells: Possible roles of iron and ROS. Carcinogenesis. 30:645–654. 2009. View Article : Google Scholar : PubMed/NCBI
9	Lin CW, Shen SC, Hou WC, Yang LY and Chen YC: Heme oxygenase-1 inhibits breast cancer invasion via suppressing the expression of matrix metalloproteinase-9. Mol Cancer Ther. 7:1195–1206. 2008. View Article : Google Scholar : PubMed/NCBI
10	Liu PL, Tsai JR, Charles AL, Hwang JJ, Chou SH, Ping YH, Lin FY, Chen YL, Hung CY, Chen WC, et al: Resveratrol inhibits human lung adenocarcinoma cell metastasis by suppressing heme oxygenase 1-mediated nuclear factor-kappaB pathway and subsequently downregulating expression of matrix metalloproteinases. Mol Nutr Food Res. 54(Suppl 2): S196–S204. 2010. View Article : Google Scholar : PubMed/NCBI
11	Heo I and Kim VN: Regulating the regulators: Posttranslational modifications of RNA silencing factors. Cell. 139:28–31. 2009. View Article : Google Scholar : PubMed/NCBI
12	Beckman JD, Chen C, Nguyen J, Thayanithy V, Subramanian S, Steer CJ and Vercellotti GM: Regulation of heme oxygenase-1 protein expression by miR-377 in combination with miR-217. J Biol Chem. 286:3194–3202. 2011. View Article : Google Scholar :
13	Qiu L, Fan H, Jin W, Zhao B, Wang Y, Ju Y, Chen L, Chen Y, Duan Z and Meng S: miR-122-induced down-regulation of HO-1 negatively affects miR-122-mediated suppression of HBV. Biochem Biophys Res Commun. 398:771–777. 2010. View Article : Google Scholar : PubMed/NCBI
14	Shan Y, Zheng J, Lambrecht RW and Bonkovsky HL: Reciprocal effects of micro-RNA-122 on expression of heme oxygenase-1 and hepatitis C virus genes in human hepatocytes. Gastroenterology. 133:1166–1174. 2007. View Article : Google Scholar : PubMed/NCBI
15	Kozakowska M, Szade K, Dulak J and Jozkowicz A: Role of heme oxygenase-1 in postnatal differentiation of stem cells: A possible cross-talk with microRNAs. Antioxid Redox Signal. 20:1827–1850. 2014. View Article : Google Scholar :
16	Yao J, Liang L, Huang S, Ding J, Tan N, Zhao Y, Yan M, Ge C, Zhang Z, Chen T, et al: MicroRNA-30d promotes tumor invasion and metastasis by targeting Galphai2 in hepatocellular carcinoma. Hepatology. 51:846–856. 2010.PubMed/NCBI
17	Chin HJ, Cho HJ, Lee TW, Na KY, Yoon HJ, Chae DW, Kim S, Jeon US, Do JY, Park JW, et al Progressive REnal disease and Medical Informatics and gEnomics Research (PREMIER) members: The heme oxygenase-1 genotype is a risk factor to renal impairment of IgA nephropathy at diagnosis, which is a strong predictor of mortality. J Korean Med Sci. 24(Suppl 1): S30–S37. 2009. View Article : Google Scholar : PubMed/NCBI
18	Sunamura M, Duda DG, Ghattas MH, Lozonschi L, Motoi F, Yamauchi J, Matsuno S, Shibahara S and Abraham NG: Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer. Angiogenesis. 6:15–24. 2003. View Article : Google Scholar : PubMed/NCBI
19	Vashist YK, Blessmann M, Trump F, Kalinin V, Kutup A, Schneider C, Gawad K, Kaifi JT, Schmelzle R, Izbicki JR, et al: Microsatellite GTn-repeat polymorphism in the promoter of heme oxygenase-1 gene is an independent predictor of tumor recurrence in male oral squamous cell carcinoma patients. J Oral Pathol Med. 37:480–484. 2008. View Article : Google Scholar : PubMed/NCBI
20	Faller M, Matsunaga M, Yin S, Loo JA and Guo F: Heme is involved in microRNA processing. Nat Struct Mol Biol. 14:23–29. 2007. View Article : Google Scholar
21	Li Y, Lin L, Li Z, Ye X, Xiong K, Aryal B, Xu Z, Paroo Z, Liu Q, He C, et al: Iron homeostasis regulates the activity of the microRNA pathway through poly(C)-binding protein 2. Cell Metab. 15:895–904. 2012. View Article : Google Scholar : PubMed/NCBI
22	Skrzypek K, Tertil M, Golda S, Ciesla M, Weglarczyk K, Collet G, Guichard A, Kozakowska M, Boczkowski J, Was H, et al: Interplay between heme oxygenase-1 and miR-378 affects non-small cell lung carcinoma growth, vascularization, and metastasis. Antioxid Redox Signal. 19:644–660. 2013. View Article : Google Scholar : PubMed/NCBI
23	Kozakowska M, Ciesla M, Stefanska A, Skrzypek K, Was H, Jazwa A, Grochot-Przeczek A, Kotlinowski J, Szymula A, Bartelik A, et al: Heme oxygenase-1 inhibits myoblast differentiation by targeting myomirs. Antioxid Redox Signal. 16:113–127. 2012. View Article : Google Scholar :
24	Martello G, Rosato A, Ferrari F, Manfrin A, Cordenonsi M, Dupont S, Enzo E, Guzzardo V, Rondina M, Spruce T, et al: A MicroRNA targeting dicer for metastasis control. Cell. 141:1195–1207. 2010. View Article : Google Scholar : PubMed/NCBI
25	Finnerty JR, Wang WX, Hébert SS, Wilfred BR, Mao G and Nelson PT: The miR-15/107 group of microRNA genes: Evolutionary biology, cellular functions, and roles in human diseases. J Mol Biol. 402:491–509. 2010. View Article : Google Scholar : PubMed/NCBI
26	Zou CD, Zhao WM, Wang XN, Li Q, Huang H, Cheng WP, Jin JF, Zhang H, Wu MJ, Tai S, et al: MicroRNA-107: A novel promoter of tumor progression that targets the CPEB3/EGFR axis in human hepatocellular carcinoma. Oncotarget. 7:266–278. 2016.
27	Cheng P, Alberts I and Li X: The role of ERK1/2 in the regulation of proliferation and differentiation of astrocytes in developing brain. Int J Dev Neurosci. 31:783–789. 2013. View Article : Google Scholar : PubMed/NCBI
28	Fu J, Lv H, Guan H, Ma X, Ji M, He N, Shi B and Hou P: Metallothionein 1G functions as a tumor suppressor in thyroid cancer through modulating the PI3K/Akt signaling pathway. BMC Cancer. 13:4622013. View Article : Google Scholar : PubMed/NCBI