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Nucleostemin Modulates Outcomes of Hepatocellular Carcinoma Via a Tumor Adaptive Mechanism to Genomic Stress Junying Wang1, Daniel J

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Nucleostemin Modulates Outcomes of Hepatocellular Carcinoma Via a Tumor Adaptive Mechanism to Genomic Stress Junying Wang1, Daniel J Published OnlineFirst February 12, 2020; DOI: 10.1158/1541-7786.MCR-19-0777 MOLECULAR CANCER RESEARCH | GENOME MAINTENANCE Nucleostemin Modulates Outcomes of Hepatocellular Carcinoma via a Tumor Adaptive Mechanism to Genomic Stress Junying Wang1, Daniel J. McGrail2, Parnit K. Bhupal1, Wen Zhang1,3, Kuan-Yu Lin1, Yi-Hsuan Ku1, Tao Lin1, Hongfu Wu1, Kyle C. Tsai4, Kaiyi Li5, Cheng-Yuan Peng6, Milton J. Finegold7, Shiaw-Yih Lin2, and Robert Y.L. Tsai1 ABSTRACT ◥ Hepatocellular carcinomas (HCC) are adapted to survive HR repair in yeasts. In support, NS-high HCCs are more reliant extreme genomic stress conditions imposed by hyperactive DNA on the replicative/oxidative stress response pathways, whereas replication and genotoxic drug treatment. The underlying NS-low HCCs depend more on the mTOR pathway. Perturbation mechanisms remain unclear, but may involve intensified DNA studies showed NS function in protecting human HCC cells from damage response/repair programs. Here, we investigate a new replication- and drug-induced DNA damage. Notably, NS deple- role of nucleostemin (NS) in allowing HCC to survive its own tion in HCC cells increases the amounts of physical DNA damage malignancy, as NS was previously shown to promote liver and cytosolic double-stranded DNA, leading to a reactive regeneration via a damage repair mechanism. We first estab- increase of cytokines and PD-L1. This study shows that NS lished that a higher NS transcript level correlates with high-HCC provides an essential mechanism for HCC to adapt to high grades and poor prognostic signatures, and is an independent genomic stress for oncogenic maintenance and propagation. NS predictor of shorter overall and progression-free survival specif- deficiency sensitizes HCC cells to chemotherapy but also triggers ically for HCC and kidney cancer but not for others. Immunos- tumor immune responses. taining confirmed that NS is most abundantly expressed in high- grade and metastatic HCCs. Genome-wide analyses revealed that Implications: HCC employs a novel, nucleostemin (NS)-mediated- NS is coenriched with MYC target and homologous recombina- mediated adaptive mechanism to survive high genomic stress con- tion (HR) repair genes in human HCC samples and functionally ditions, a deficiency of which sensitizes HCC cells to chemotherapy intersects with those involved in replication stress response and but also triggers tumor immune responses. Introduction (two-third) due to high incidence of relapse and metastasis as well as resistance to radiation and drug therapies. Hepatocellular carcinoma (HCC) is the sixth most common cancer Drug resistance poses a major obstacle for HCC treatment. Con- and third leading cause of cancer-related death worldwide (1). It ventional chemotherapies have been proven ineffective individually or accounts for up to half of all cancers in Southeast Asia and has become in combination. Current approved therapies for advanced HCC the fastest growing lethal cancer in the United States. HCC may be include the first-line sorafenib and lenvatinib (FDA-approved on treated by surgical resection, local ablation, or transplantation at the August1 16, 2018) and the second-line regorafenib, cabozantinib, early stage (one-third) but becomes incurable at the advanced stage nivolumab, and pembrolizumab. Sorafenib alone improves patients’ survival by 3 months (2, 3). Nivolumab is moderately effective but only for selected patients (19%; ref. 4), reflecting the difficulty in developing 1Institute of Biosciences and Technology, Texas A&M University, Houston, Texas. targeted therapies for tumors with multiple oncogenic drivers, such as 2Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas. HCC. We reason that regardless of their many etiologies and muta- 3Department of Integrative Medicine, Zhongshan Hospital, Fudan University, tions, the progression of HCCs would inevitably involve hyperactive 4 Shanghai, China. Michael E. DeBakey High School for Health Professions, cell division, leading to replication stress. Thus, determining the Houston, Texas. 5Department of Surgery, Baylor College of Medicine, Houston, 6 tumor-addicted mechanism(s) that enables HCCs to adapt to and Texas. Division of Hepatogastroenterology, Department of Internal Medicine, – China Medical University Hospital, School of Medicine, China Medical University, evade replication stress induced catastrophe (also known as Achilles fi fi Taichung, Taiwan. 7Department of Pathology & Immunology, Baylor College of heel) may provide a rst step toward nding a universal target to Medicine, Houston, Texas. mitigate the mortality of advanced HCCs. Recent studies have indi- fi Note: Supplementary data for this article are available at Molecular Cancer cated that genome maintenance may be bene cial for tumor progres- Research Online (http://mcr.aacrjournals.org/). sion at the late stage (5–7). So far, these findings were primarily made in breast and ovarian cancers. D.J. McGrail and P.K. Bhupal contribute equally to this article. One protein that could help HCC cope with excess replication stress Corresponding Author: Robert Y.L. Tsai, Texas A&M Health Science Center, is nucleostemin (NS), a GTP-binding nucleolar protein first discovered 2121 W. Holcombe Blvd., Rm 517, Houston, TX 77030. Phone: 713-677-7690; – Fax: 713-677-7512; E-mail: [email protected] in neural and embryonic stem cells (8 10) and later found at high levels in other types of stem cells and cancers (8, 11). Our initial interest in NS – Mol Cancer Res 2020;XX:XX XX was driven by its role in stem cell self-renewal. A series of our work doi: 10.1158/1541-7786.MCR-19-0777 reveal that the primary activity of NS in stem cells is to protect the Ó2020 American Association for Cancer Research. integrity of replicating genome (9, 12–14). Recent studies have AACRJournals.org | OF1 Downloaded from mcr.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst February 12, 2020; DOI: 10.1158/1541-7786.MCR-19-0777 Wang et al. independently shown that the ability of cancer stem cells to respond to with 5-fluorouracil (5-FU; 10 mg/mL), oxaliplatin (10 mmol/L), doxo- DNA damage is more intensified as compared with nonstem cancer rubicin (5 mmol/L), or olaparib (200 mmol/L). – cells, resulting in enhanced DNA repair and G2 M-phase checkpoint activation, which may contribute to tumor resistance to replication stress and chemo/radiotherapies (15). We speculate that NS may serve Results an essential mechanism for HCC to survive extreme genomic stress High NS expression correlates with high-tumor grades and poor conditions. The role of NS in liver pathophysiology has been previ- prognosis and survival in patients with HCC ously indicated by: (i) NS expression is upregulated in hepatic pre- To establish the clinical relevance of NS in HCC, we first compared cursor cells and regenerating adult hepatocytes (12, 16), (ii) NS its total transcript levels between human HCC (n ¼ 369) and adjacent depletion sensitizes MHCC97 cells to UV and serum starvation– nontumor tissues (ANT, n ¼ 64). On the basis of the TCGA HCC induced apoptosis (17), and (iii) high NS expression correlates with cohorts, there is a significant increase of NS in HCC compared with poor survival (18) and sorafenib resistance in patients with HCC (19). ANT (Fig. 1A). From a pan-cancer perspective, HCC is ranked among Our current data show that NS correlates with tumor grade and the top tertile in NS expression (Supplementary Fig. S1A). Comparing uniquely predicts both overall survival (OS) and progression-free against various clinicopathologic parameters, NS expression shows a survival (PFS) in patients with HCC. In addition, NS protects HCCs significant increase in WHO grade 3 tumors (G3, poorly differenti- from drug-induced DNA damage, and NS-high HCCs are more ated) compared with G1 (well differentiated) and G2 (moderately addicted to stress response pathways than NS-low HCCs. Notably, differentiated; P < 0.001; Fig. 1B1). Despite the low-case number of NS depletion increases the amount of physical DNA damage and undifferentiated HCCs (G4; n ¼ 12), it still shows the highest level of cytoplasmic accumulation of fragmented double-stranded DNA NS expression (Fig. 1B2). HCCs with vascular macroinvasion (n ¼ 14) (dsDNA), triggering innate immune responses in HCC cells. These express more NS than do those with none or microinvasion (Fig. 1C). results raise NS as a new HCC outcome predictor and a potential We also found that NS expression in HCC correlates positively therapeutic target for sensitizing HCCs to conventional chemotherapy with serum a-fetoprotein, fibrosis score, or viral hepatitis, but not as well as immunotherapy. with clinical stages (Supplementary Fig. S1B–S1E). To determine whether the NS level is prognostic of the clinical outcome of patients with HCC, we compared it in different molecular categories of Materials and Methods HCC (21), and found that NS is expressed: (i) more in the S2 Animal care and procedures (aggressive, Myc/Akt-activated) than in the S1 (aggressive, TGF- Animals were housed by the Program for Animal Resources at the b-activated) or S3 (differentiated) subtype based on the Hoshida Texas A&M Health Science Center-Houston campus (Houston, TX) classification (22), (ii) more in the robust cluster 2 (C2, advanced and handled in accordance with the principles described by the Guide tumors with more vascular invasion and extrahepatic metastasis) than for the Care and Use of Laboratory Animals. All procedures were in the C1 subtype based on the hepatoblastoma classification (23), and approved by the Institutional Animal Care and Use Committee. (iii) more in the A (proliferation/unfavorable) than in the B subclass by the NCI proliferation classification (ref. 24; Fig. 1D). Finally, univar- TCGA and Gene set enrichment analyses iate log-rank analyses demonstrated that patients with NS-high HCCs Processed RNA-seq gene expression data for HCC were acquired (n ¼ 182, G1/G2/G3/G4 ¼ 20/76/75/11, stage 1/2/3/4 ¼ 80/50/42/3, through the GDC data portal (https://portal.gdc.cancer.gov/). Other age 16–85) show shorter OS or PFS, compared with those with NS-low data were acquired through cBioPortal.
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