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Cell Cycle Arrest Protein CDKN2C Is Not an HBV Host Factor

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Cell Cycle Arrest Protein CDKN2C Is Not an HBV Host Factor Virologica Sinica www.virosin.org https://doi.org/10.1007/s12250-020-00337-9 www.springer.com/12250 (0123456789().,-volV)(0123456789().,-volV) LETTER Cell Cycle Arrest Protein CDKN2C Is Not an HBV Host Factor 1,2 2 2 2 2 1,2 Guiwen Guan • Liwei Zheng • Jingyuan Xi • Xingwen Yang • Xiangmei Chen • Fengmin Lu Received: 27 July 2020 / Accepted: 16 November 2020 Ó Wuhan Institute of Virology, CAS 2021 Dear Editor, between CDKN2C expression and HBV load in CHB patients was analyzed by use of the data of 90 CHB Hepatitis B virus (HBV) infection remains a major cause of patients in GSE83148 dataset (Zhou et al. 2017), yet no liver diseases worldwide, which affects approximately 250 significant difference of CDKN2C expression between million people globally (Yuen et al. 2018). Individuals patients with HBV DNA load \ lg106 IU/mL and those with chronic HBV infection are at high risk of developing with C lg106 IU/mL (Fig. 1A) was observed. To consoli- liver cirrhosis, and ultimately hepatocellular carcinoma date our finding, GSE84044 (Wang et al. 2017), the liver (HCC). HBV is a Hepadnavirus DNA virus, which transcriptome dataset from another 124 patients with HBV- specifically infects and efficiently replicates in hepatocytes. related liver fibrosis was also analyzed. Either, no corre- It has been proposed for decades that HBV replicates lation between hepatic CDKN2C expression levels and preferentially in non-dividing quiescent hepatocytes (Ozer serum HBV DNA load was observed (r = 0.115, et al. 1996), therefore remarkably influenced by cell P = 0.255) (Fig. 1B). Next, a third dataset of GSE94660 growth and proliferation status. In line with this, a recent (Yoo et al. 2017) composing of RNA-seq data from 21 study by Carla Eller et al.(2020) reported that by utilizing HBV infection-related HCC patients was analyzed. Simi- a genome-wide gain-of-function screen, CDKN2C, the larly, liver CDKN2C expression showed no correlation inhibitor of cyclin D (CDK4/6), was identified as an HBV with HBV RNA levels in the malignant hepatocellular host factor favoring viral replication via cell cycle arrest. In carcinoma tissues either (r = 0.367, P = 0.107) (Fig. 1C). their study, cell cycle arrest is essential for generating a It has been reported that the expression of CDKN2C was prerequisite cellular environment for CDKN2C to enhance markedly upregulated when cells reach G1/S transition and HBV replication. Nevertheless, given the fact that the progress through the remainder of the cycle (Hirai et al. stealth HBV replicates most efficiently in the quiescent 1995). Increased expression of CDKN2C has also been hepatocytes in the immune tolerance phase, it remains to be shown to be coordinated with the terminal differentiation validated whether CDKN2C virtually serves as an HBV of adipocytes (Morrison and Farmer 1999). To explore the host factor. relationship between CDKN2C expression level and hep- To reevaluate the role of CDKN2C in HBV replication atocyte proliferation status in CHB patients, we first in patients of chronic hepatitis B (CHB), the relationship developed a cell proliferating index model through factor analysis, utilizing the gene expression status of 92 out of Electronic supplementary material The online version of this article the 116 KEGG annotated cell cycle related genes (https://doi.org/10.1007/s12250-020-00337-9) contains supplemen- (ko04110, http://www.kegg.jp) available in GSE83148 tary material, which is available to authorized users. dataset. This novel index could reflect the proliferation status of hepatocytes with good performance, as it was well & Fengmin Lu [email protected] positively correlated with Ki-67 levels (r = 0.759, P \ 0.001) in the liver tissues of these CHB patients & Xiangmei Chen [email protected] (Fig. 1D). Intriguingly, the cell proliferating index was significantly higher in patients with higher serum ALT 1 Peking University People’s Hospital, Peking University levels than those with normal levels (UNL, 40 IU/mL) Hepatology Institute, Beijing Key Laboratory of Hepatitis C (Fig. 1E), indicating that necro-inflammatory injury causes and Immunotherapy for Liver Diseases, Beijing 100044, China hepatocyte compensatory proliferation. As expected, the score of cell proliferation index is significantly negatively 2 Department of Microbiology & Infectious Disease Center, School of Basic Medical Sciences, Peking University Health correlated with HBV-dependent host gene HNF4a Science Center, Beijing 100191, China (r = -0.628, P \ 0.001) (Fig. 1F), in consistent with the 123 Virologica Sinica A B C D GSE83148 (CHB) GSE84044 (hepatic fibrosis) GSE94660 (HBV related HCC) 8 12 60 7 ns r=0.115, P=0.255 r=0.367, P=0.107 r=0.759, P<0.001 7 6 8 40 6 5 4 20 Liver Ki-67 5 4 Liver CDKN2C level HCC tissue HBV RNA Serum HBV Serum HBV DNA (log10) 4 0 0 3 4.5 5.0 5.5 6.0 6.5 0481216 -1 1 2 3 <106 IU/mL ≥106 IU/mL 0 Serum HBV DNA level Liver CDKN2C level Liver CDKN2C level Cell proliferation index HNF4α CDKN2C HNF4α EGF P H 4 11 P 8 r=0.562, <0.001 11 P P<0.001 r=-0.628, <0.001 r=-0.314, <0.001 7 2 10 10 6 9 0 9 5 Liver HNF4α level Liver HNF4α level Liver CDKN2C level Cell proliferation index -2 8 4 8 -1 0 1 2 3 -1 0 1 2 3 567 8 ALT<40 ALT≥40 Cell proliferation index Liver CDKN2C level Serum ALT level (IU/mL) Cell proliferation index I NTCP JKP P 13 3000 Vector vs. HNF4α <0.001 8 Vector vs. HNF4α <0.001 r=-0.280, P=0.002 Vector vs. CDKN2C P=0.935 Vector vs. CDKN2C P=0.235 2000 L 6 12 1000 4 BsAg IU/mL BsAg 11 H 80 HBeAg PEIU/m HBeAg Liver NTCP level Liver NTCP 2 40 10 0 0 5 6 7 8 03610 03610 Liver CDKN2C level Days post HDI Days post HDI Vector (n=9) HNF4α (n=9) CDKN2C (n=10) CDK L CC ABL T YWH E2F P5 1 SMC6 CC ND3 4 1 R SFN ND AE 3 TT BL 2 Y K 1 SMC5 CDK WHA TF N1A Z SM DP1 DDB1 APC2AD2 CDKN2A APOBEC3G CDC2 E2F3 5A CDC25B HNF1A CDKN1C CDKN2C FOXM1 TGFB2 CDK4 BUB1B HLF PLK1 CDC25C PCNA PPARa E2F5 TGFB1 MCM2 HNF4a CDKN2D TFDP2 GSK3B NTCP CUL1 YWHAB CDK2 SMC3 MCM3 CCNH MCM5 RBL2 BUB3 PRKDC YWHAG SKP1 CDC7 CDK7 MCM6 MAD2L2 CDC20 ORC4 E2F2 MDM2 STAG1 CHEK1 SMAD3 ATM CCNB2 YWHAH CDK6 SMAD4 RBX1 SKP2 MCM7 CDKN2B ORC5 CCND1 CHEK2 CCNCDC6 Cell cycle gene CDC45 C2 YWHAQORC1 B3 HDA 3 0 ZB ORC 1B TB C W ATR 1 1 2 RB1 EE1 17 BUB B 3 30 H1 4 Y HBV related gene CCN P CD FB AC1 F1 AG KN RC6 2 T M TG ORC2 D E MCMO E S H CD 123 G. Guan et al.: CDKN2C Is Not an HBV Host Factor b Fig. 1 CDKN2C is not an HBV favoring host factor. A CDKN2C CDKN2C is not positively correlated with the expression 6 expression level in CHB patients with serum HBV DNA \ lg10 IU/ of HBV-dependent genes in the liver tissues of CHB mL and those with C lg106 IU/mL in GSE83148 dataset. B Relation- ship between liver CDKN2C expression level and serum HBV DNA patients, it is rather unlikely for CDKN2C to enhance HBV for patients with HBV-related liver fibrosis in GSE84044 dataset. replication via upregulating these HBV-related host factor C Correlation between CDKN2C expression level (FPKM) and liver genes. Because most of the liver cells are in a quiescent HBV RNA level for HCC tissues in GSE94660 dataset. D Correlation (G0) state, we assume that CDKN2C cannot play the role between liver cell proliferation index and expression of Ki-67 in GSE83148 dataset. E Comparison of liver cell proliferation index in of inhibiting cell proliferation and promoting HBV repli- patients with chronic hepatitis B with different serum ALT levels in cation in vivo. To verify this hypothesis, we injected the GSE83148 dataset. F, G Correlation between liver cell proliferation HNF4a or CDKN2C expressing plasmids together with the index and expression of HNF4a and CDKN2C in GSE83148 dataset. same amount of 1.2mer HBV plasmids respectively into H, I Correlation between liver CDKN2C level and HNF4a, and NTCP expression level in GSE83148 dataset. J, K Serum HBsAg and mice through tail vein hydrodynamic injection (HI), and HBeAg levels at different time points after the mouse tail vein vector pcDNA3.1 was used as control. The mouse serum hydrodynamic injection. L Analysis of expression correlation was collected at 3, 6, and 10 days after HI, and the levels of between cell cycle related genes and HBV-dependent host genes. HBeAg and HBsAg in the serum were measured. As Blue dots represent cell cycle genes and pink dots represent HBV- dependent host genes. The line between the two points indicates that expected, the levels of HBeAg and HBsAg in the HNF4a the expression levels of the two genes are highly correlated with the group are more than 15 times higher than that of the con- cut-off values |r| [ 0.4 and fdr \ 0.05. trol, but there is no significant difference between the CDKN2C group and control group (Fig. 1J, 1K). The above results indicate that CDKN2C cannot promote HBV previous report (Hanse et al. 2012). However, contrary to replication in vivo. Thereafter, we further investigated the Eller et al.’s report (Eller et al. 2020), the expression of relationship between other known cell cycle related genes CDKN2C was found significantly positively correlated and HBV-dependent host genes (NTCP, HNF4a, HLF, with the cell proliferation index (r = 0.562, P \ 0.001) in PPARa, HNF-1, HNF-3, APOBEC3, DDB1, SMC5, and the liver tissue specimens derived from CHB patients SMC6) (Leupin et al.
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