Location: Cleveland Clinic Main Campus
My lab investigates the role of DNA repair pathway and non-coding RNAs in the development of cancer, drug resistant and side effect with the goal of designing new prevention and therapeutic strategies for cancer. Increasingly, evidence shows that a super family of non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are involved in cell differentiation, proliferation, and apoptosis by targeting protein-coding genes, and therefore are involved in cancer pathogenesis. My research group had worked on projects related to this topic and functionally identifying the key downstream protein targets of miRNAs/lncRNAs related to cancer progression. We are characterizing novel lncRNAs- related to cancer initiation, progression, and drug resistance. We also recently demonstrated for the first time that combined expression of multiple multiple myeloma (MM) driver events generates murine MM that is highly faithful to the human disease.
Chemo- or Radio- therapy induced toxicities such as nephro-, oto-, cardio-, or neuro-toxicities are major clinical problems in cancer patents receiving those treatments, but the mechanism is not fully understood. We have determined that both oxidative stress and mitochondrial damage are associated with upregulated levels of renal apurinic/apyrimidinic endonuclease 2 (APE2) in normal tissues. We also discovered that cisplatin exposure in vivo increases expression of APE2 in exposed mice and inhibits the function of myosin heavy chain 9 (MYH9), a key regulatory molecule of kidney function. We had recently developed a novel APE2 GEMM mouse models that recapitulate human cisplatin-related acute kidney injury (C-AKI) for preclinical studies. We are completely defining the APE2 mouse model phenotype and compare it with the C-AKI model for pathophysiological features at the molecular level using whole genomic, transcriptional, and immunomic approaches. The long-term goal is to test novel therapeutic target for cancer patients and ultimately translate the knowledge gained to improved cancer treatments or prevent side effects such C-AKI.
The current efforts of my lab are focused on two distinct but interactive directions that include:
1) Preclinical GEM mouse models of multiple myeloma for immunotherapies evaluation.
2) Preclinical murine models of chemo- or radio- therapy related toxicities including nephro-, oto-, cardio-, and neuro-toxicities.
Both of these models feature diverse topics that include DNA damage repair pathway genes, mitochondrial function dyregulation, genomic instability, noncoding RNA, and novel monoclonal antibody or nanobody drug discovery.
For example, we recently demonstrated that combined expression of more than a single putative multiple myeloma (MM) driver event identified from unbiased sequencing of MM patient samples generates MM disease in mice that is highly faithful to the human disease. Secondly, we found that inhibiting the DNA repair gene APE2 in a preclinical model of cisplatin-induced acute kidney injury significantly attenuated disease pathology. Thirdly, another study performed in my lab suggested that the FDA-approved CD38 mAb drug daratumumab sensitivity may be restored by the use of miR-26a, a microRNA that has been shown to be a tumor suppressor. Lastly, my lab also discovered a novel role for the repair proteins PARP1 and LIG3 in the MALAT1-dependent A-NHEJ pathway, implicating MALAT1 dysregulation as an important mechanism in the initiation of MM.
Chen G, Zhao X, Dankovskyy M, Ansah-Zame A, Alghamdi U, Liu D, Wei R, Zhao J, Zhou A. A novel role of RNase L in the development of nonalcoholic steatohepatitis. FASEB J. 2023 Sep;37(9):e23158. doi: 10.1096/fj.202300621R.
Hao J, Han X, Huang H, Yu X, Fang J, Zhao J, Prayson RA, Bao S, Yu JS. Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma. Nat Commun. 2023 Apr 20;14(1):2262. doi: 10.1038/s41467-023-37397-w.
McMahon A, Zhao J, Yan S. APE2: catalytic function and synthetic lethality draw attention as a cancer therapy target. NAR Cancer. 2023 Feb 6;5(1):zcad006. doi: 10.1093/narcan/zcad006. eCollection 2023 Mar.
Sadaf H, Hong H, Maqbool M, Emhoff K, Lin J, Yan S, Anwer F, Zhao J. Multiple myeloma etiology and treatment. Journal of Translational Genetics and Genomics. 2022, 6: 63-83.
Hu Y, Yang C, Amorim T, Maqbool M, Lin J, Li C, Fang C, Xue Li, Kwart A, Fang H, Yin M, Janocha AJ, Tsuchimoto D,Nakabeppu Y, Jiang X, Mejia-Garcia A, Anwer F, Khouri J, Qi X, Zheng QY, Yu JS, Yan S, LaFramboise T, AndersonKC, Herlitz LC, Munshi NC, Lin J, Zhao J. Cisplatin-mediated upregulation of apurinic/apyrimidinic endonuclease 2 (APE2) binding to myosin heavy-chain 9 (MYH9) provokes mitochondrial fragmentation and acute kidney injury. Cancer Research. 2021 Feb 1;81(3):713-723. doi: 10.1158/0008-5472.CAN-20-1010. Epub 2020 Dec 7. PMID: 33288657. PMCID: PMC7869671.
Hossain A, Lin Y, Driscoll G, Li J, Mcmahon A, Matos J, Zhao H, Tsuchimoto D, Nakabeppu Y, Zhao J, Yan S. APE2 is a general regulator of the ATR-Chk1 DNA damage response pathway to maintain genome integrity in pancreatic cancer cells. Frontiers Cell and Developmental Biology. 2021, 9:738502. PMCID: PMC8593216; PMID: 34796173.
Yang C, Lin J, Liang H, Xue L, Jiang M, Kwart A, Zhao J, Ren H, Jiang X, Munshi N. CD44 v5 domain Inhibition Represses the Polarization of Th2 Cell by Interfering with the IL-4/IL-4R Signaling Pathway. Immunol Cell Biol. 2021 Jul 5. doi: 10.1111/imcb.12491. Online ahead of print. PMID: 34219288
George LL, Deshpande SR, Cortese MJ, Kendall EK, Chattaraj A, Shah Z, Zhao J, Anwer F. Emerging Targets and Cellular Therapy for Relapsed Refractory Multiple Myeloma: A Systematic Review. Clinical Lymphoma, Myeloma and Leukemia. Published:June 14, 2021 DOI: https://doi.org/10.1016/j.clml.2021.06.003
Sewastianik T, Straubhaar JR, Zhao J, Samur MK, Adler K, Tanton H, Shanmugam V, Nadeem O, Dennis P, Pillai V, Wang J, Jiang M, Lin J, Huang Y, Brooks DJ, Bouxsein M, Dorfman D, Pinkus GS, Robbiani DF, Ghobrial IM, Budnik B, Jarolim P, Munshi NC, Anderson KC, Carrasco DR. miR-15a/16-1 deletion in activated B-cells promotes plasma cell and mature B-cell neoplasms. Blood. 2021 Jan 13:blood.2020009088. doi: 10.1182/blood.2020009088. PMID: 33751108
Huang H, Yu X, Han X, Hao J, Zhao J, Bebek G, Bao S, Prayson RA, Khalil AM, Jankowsky E, Yu JS. Piwil1 Regulates Glioma Stem Cell Maintenance and Glioblastoma Progression. Cell Report. 2021 Jan 5;34(1):108522. doi: 10.1016/j.celrep.2020.108522.
Hu Y, Liu H, Fang C, Li C, Xhyliu F, Dysert H, Bodo J, Habermehl G, Russell B, Li W, Chappell M, Jiang X, Ondrejka S, Hsi E, Maciejewski JP, Yi Q, Anderson KC, Munshi NC, Ao G, Valent JN, Lin J, Zhao J. Targeting of CD38 by the Tumor Suppressor miR-26a Serves as a Novel Potential Therapeutic Agent in Multiple Myeloma. Cancer Research. 2020 May 15;80(10):2031-2044. doi: 10.1158/0008-5472.CAN-19-1077.Epub 2020 Mar 19. PMID: 32193289. PMCID: PMC7231653.
Hu B , Liu Y, Chen X, Zhao J, Han J, Dong H, Zheng Q, Nie G. Ferrostatin-1 protects auditory hair cells from cisplatin-induced ototoxicity in vitro and in vivo. Biochem Biophys Res Commun. 2020 Dec 17;533(4):1442-1448. PMID: 33109343.
Lin Y, McMahona A, Driscolla G, Bullocka S, Zhao J, Yan S. Function and molecular mechanisms of APE2 in genome and epigenome integrity. Mutation Research-Reviews in Mutation Research (MUTREV). 2020, 108347. Online ahead of print.
Usman RM, Razzaq F, Akbar A, Farooqui AA, Iftikhar A, Latif A, Hassan H, Zhao J, Carew JS, Nawrocki ST, Anwer F. Role and mechanism of autophagy-regulating factors in tumorigenesis and drug resistance. Asia Pac J Clin Oncol. 2020 Sep 24. doi: 10.1111/ajco.13449. Online ahead of print.
Lin J, Hu Y, Zhao J. Repression of Multiple Myeloma Cell Growth In Vivo by Single-wall Carbon Nanotube (SWCNT)-delivered MALAT1 Antisense Oligos. Jove. 2018 July 31. e58598, doi:10.3791/58598.
Hu Y, Lin J, Fang H, Fang J, Li C, Chen W, Liu S, Ondrejka S, Gong Z, Maciejewski J, Reu F, Yi Q, Zhao J. Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma. Leukemia. 2018 Oct; 32(10):2250-2262. doi: 10.1038/s41375-018-0104-2. Epub 2018 Mar 22. PMID: 29632340. PMCID: PMC6151178. https://www.nature.com/articles/s41375-018-0104-2.
Lin J, Zhang W, Zhao J, Kwart AH, Yang C, Ma D, Ren X, Tai YT, Anderson KC, Handin RI, Munshi NC. A clinically relevant in vivo zebrafish model of human multiple myeloma to study preclinical therapeutic efficacy. Blood. 2016 Jul 14;128(2):249-52. doi: 10.1182/blood-2016-03-704460. PMID: 27207793.
Liu S, An J, Lin J, Liu Y, Bao L, Zhang W, Zhao J. Single nucleotide polymorphisms of microRNA processing machinery genes and outcome of hepatocellular carcinoma. Plos One. 2014 Mar 27;9(3):e92791.
Zhao J, Chu ZB, Hu Y, Lin J, Wang Z, Jiang M, Chen M, Wang X, Zhou Y, Chonghaile TN, Johncilla ME, Tai YT, Cheng JQ, Letai A, Munshi NC, Anderson KC, Carrasco RD. Targeting the miR-221-222/PUMA/BAK/BAX Pathway Abrogates Dexamethasone Resistance in Multiple Myeloma. Cancer Research. 2015 Oct 15;75(20):4384-97.
Zhu D, Wang Z, Zhao J, Calimeri T, Meng J, Hideshima T, Fulciniti M, Kang Y, Ficarro SB, Tai YT, Hunter Z, McMillin D, Tong H, Mitsiades CS, Wu CJ, Treon SP, Dorfman DM, Pinkus G, Munshi NC, Tassone P, Marto JA, Anderson KC, Carrasco RD. The Cyclophilin A-CD147 complex promotes the proliferation and homing of multiple myeloma cells. Nature Medicine. 2015 Jun;21(6):572-80.
Zhao J, Carrasco DR. Crosstalk between microRNA30a/b/c/d/e-5p and the canonical Wnt pathway: implications for multiple myeloma therapy. Cancer Research. 2014 Oct 1;74(19):5351-8. (invited review)
Zhao J, Lin J, Zhu D, Wang X, Brooks D, Chen M, Chu ZB, Takada K, Ciccarelli B, Admin S, Tao J, Tai YZ, Treon S, Pinkus G, Kuo WP, Hideshima T, Bouxsein M, Munshi N, Anderson K, Carrasco DR. miR-30-5p functions as a tumor suppressor and novel therapeutic tool by targeting the oncogenic Wnt/β-catenin/BCL9 pathway. Cancer Research. 2014 Mar 15;74(6):1801-13.
Tian Z, Zhao J, Tai YZ, Amin S, Hu Y, Richardson PG, Anderson KC. Investigational agent MLN9708/2238 targets tumor-suppressor miR33b in MM cells. Blood. 2012 Nov 8;120(19):3958-67.
Takada K, Zhu D, Bird G, Sukhdeo K, Zhao J, Mani M, Lemieux M, Carrasco D, Horst D, Fulciniti M, Munshi N, Xu W, Kung A, Shivdasani R, Walensky L, Carrasco DR.Targeted disruption of the BCL9/β-catenin complex inhibits oncogenic Wnt signaling. Science Translational Medicine. 2012; 4:148, p. 148ra117.
Tai YT, Chang BY, Kong SY, Fulciniti M, Yang G, Calle Y, Hu Y, Lin J, Zhao J, Cagnetta A, Cea M, Sellitto MA, Zhong MY, Wang Q, Acharya C, Carrasco DR, Buggy JJ, Elias L, Treon SP, Matsui W, Richardson P, Munshi NC, Anderson KC. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood. 2012 Aug 30;120(9):1877-87.
Lin J, Lwin T, Zhao J, Tam W, Choi YS, Moscinski LC, Dalton WS, Sotomayor EM, Wright KL, Tao J. Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin's B-cell lymphomas. Leukemia. 2011, Jan;25(1):145-52.
Zhao J, Lin J, Lwin Tint, Guo J, Dalton SW, Sotomayor E, Tao J, Cheng JQ. microRNA expression profile and identification of miR-29 as a prognostic marker and pathogenetic factor by targeting CDK6 in mantle cell lymphoma. Blood. 2010, 1; 115(13): 2630-9.
Research Fellow Position Available: Our group is seeking highly motivated research fellows to join our studies to develop novel immune therapy for multiple myeloma. The position will provide a unique and multidisciplinary exposure to preclinical mouse models, molecular oncology, immune therapy, drug development and clinical trials. The ideal candidate has a MD or PhD degree in clinical medicine, biochemistry or molecular biology; has the appropriate expertise in mouse model is highly encouraged to apply. Outstanding verbal and communication skills are required. Interested applicants should submit a CV and contact information for 3 references to Dr. Jianjun Zhao via email: firstname.lastname@example.org
Our education and training programs offer hands-on experience at one of the nationʼs top hospitals. Travel, publish in high impact journals and collaborate with investigators to solve real-world biomedical research questions.Learn More
Drs. Yu and Zhao will study the role of a long non-coding RNA called Lucat1 in glioma stem cells in the search for new therapeutics to help treat glioblastoma and overcome treatment resistance.
The National Cancer Institute awarded Dr. Zhao $2.6 million dollars to continue research that seeks to develop treatment options for acute kidney injury that can commonly result as a side effect of chemotherapy.
Dr. Zhao and his team found that inhibiting the APE2 protein in a preclinical model of cisplatin-induced acute kidney injury significantly helped attenuate disease pathology.
Dr. Zhao found that sensitivity to daratumumab, an approved multiple myeloma treatment, may be rescued and restored using miR-26a.