Uncovering miRNA-mRNA Regulatory Networks Related to Olaparib Resistance and Resensitization of BRCA2MUT Ovarian Cancer PEO1-OR Cells with the ATR/CHK1 Pathway Inhibitors

被引：0

作者：

Biegala, Lukasz ^{[1
,2
]}

Kolat, Damian ^{[3
,4
]}

Gajek, Arkadiusz ^{[1
]}

Pluciennik, Elzbieta ^{[3
]}

Marczak, Agnieszka ^{[1
]}

Sliwinska, Agnieszka ^{[5
]}

Mikula, Michal ^{[6
]}

Rogalska, Aneta ^{[1
]}

机构：

[1] Univ Lodz, Inst Biophys, Fac Biol & Environm Protect, Dept Med Biophys, Pomorska 141-143, PL-90236 Lodz, Poland

[2] Univ Lodz, Doctoral Sch Exact & Nat Sci, Jana Matejki 21-23, PL-90237 Lodz, Poland

[3] Med Univ Lodz, Dept Funct Genom, Zeligowskiego 7-9, PL-90752 Lodz, Poland

[4] Med Univ Lodz, Dept Biomed & Expt Surg, Narutowicza 60, PL-90136 Lodz, Poland

[5] Med Univ Lodz, Dept Nucl Acid Biochem, Pomorska 251, PL-92213 Lodz, Poland

[6] Maria Sklodowska Curie Natl Res Inst Oncol, Dept Genet, Roentgena 5, PL-02781 Warsaw, Poland

来源：

CELLS | 2024年 / 13卷 / 10期

关键词：

ovarian cancer; miRNA profiling; olaparib; resistance; ATR/CHK1; pathway; combination therapy; growth factors; bioinformatics; TCGA data; EXPRESSION; 14-3-3-SIGMA; SENSITIVITY; RESOURCE; PARP-1;

D O I：

10.3390/cells13100867

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Resistance to olaparib is the major obstacle in targeted therapy for ovarian cancer (OC) with poly(ADP-ribose) polymerase inhibitors (PARPis), prompting studies on novel combination therapies to enhance olaparib efficacy. Despite identifying various mechanisms, understanding how OC cells acquire PARPi resistance remains incomplete. This study investigated microRNA (miRNA) expression in olaparib-sensitive (PEO1, PEO4) and previously established olaparib-resistant OC cell lines (PEO1-OR) using high-throughput RT-qPCR and bioinformatic analyses. The role of miRNAs was explored regarding acquired resistance and resensitization with the ATR/CHK1 pathway inhibitors. Differentially expressed miRNAs were used to construct miRNA-mRNA regulatory networks and perform functional enrichment analyses for target genes with miRNet 2.0. TCGA-OV dataset was analyzed to explore the prognostic value of selected miRNAs and target genes in clinical samples. We identified potential processes associated with olaparib resistance, including cell proliferation, migration, cell cycle, and growth factor signaling. Resensitized PEO1-OR cells were enriched in growth factor signaling via PDGF, EGFR, FGFR1, VEGFR2, and TGF beta R, regulation of the cell cycle via the G2/M checkpoint, and caspase-mediated apoptosis. Antibody microarray analysis confirmed dysregulated growth factor expression. The addition of the ATR/CHK1 pathway inhibitors to olaparib downregulated FGF4, FGF6, NT-4, PLGF, and TGF beta 1 exclusively in PEO1-OR cells. Survival and differential expression analyses for serous OC patients revealed prognostic miRNAs likely associated with olaparib resistance (miR-99b-5p, miR-424-3p, and miR-505-5p) and resensitization to olaparib (miR-324-5p and miR-424-3p). Essential miRNA-mRNA interactions were reconstructed based on prognostic miRNAs and target genes. In conclusion, our data highlight distinct miRNA profiles in olaparib-sensitive and olaparib-resistant cells, offering molecular insights into overcoming resistance with the ATR/CHK1 inhibitors in OC. Moreover, some miRNAs might serve as potential predictive signature molecules of resistance and therapeutic response.

引用

页数：31

共 72 条

[21] Cancer-associated fibroblast-derived exosomal microRNA-98-5p promotes cisplatin resistance in ovarian cancer by targeting CDKN1A [J].

Guo, Hua ;

Ha, Chunfang ;

Dong, Hui ;

Yang, Zhijuan ;

Ma, Yuan ;

Ding, Yonghui .

CANCER CELL INTERNATIONAL, 2019, 19 (01)

[22] Comprehensive analysis of key genes and microRNAs in radioresistant nasopharyngeal carcinoma [J].

Guo, Ya ;

Zhang, Yang ;

Zhang, Shu Juan ;

Ma, Yi Nan ;

He, Yun .

BMC MEDICAL GENOMICS, 2019, 12

[23] Efficacy and safety of VEGF/VEGFR inhibitors for platinum-resistant ovarian cancer: a systematic review and meta-analysis of randomized controlled trials [J].

Huang, Danxue ;

Ke, Liyuan ;

Cui, Hongxia ;

Li, Su ;

Sun, Feilong .

BMC WOMENS HEALTH, 2024, 24 (01)

[24] Loss of MED12 activates the TGFβ pathway to promote chemoresistance and replication fork stability in BRCA-deficient cells [J].

Jackson, Lindsey M. ;

Dhoonmoon, Ashna ;

Hale, Anastasia ;

Dennis, Kady A. ;

Schleicher, Emily M. ;

Nicolae, Claudia M. ;

Moldovan, George-Lucian .

NUCLEIC ACIDS RESEARCH, 2021, 49 (22) :12855-12869

[25] Deregulated miRNA clusters in ovarian cancer: Imperative implications in personalized medicine [J].

Kandettu, Amoolya ;

Adiga, Divya ;

Devi, Vasudha ;

Suresh, Padmanaban S. ;

Chakrabarty, Sanjiban ;

Radhakrishnan, Raghu ;

Kabekkodu, Shama Prasada .

GENES & DISEASES, 2022, 9 (06) :1443-1465

[26] Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models [J].

Kim, Hyoung ;

Xu, Haineng ;

George, Erin ;

Hallberg, Dorothy ;

Kumar, Sushil ;

Jagannathan, Veena ;

Medvedev, Sergey ;

Kinose, Yasuto ;

Devins, Kyle ;

Verma, Priyanka ;

Ly, Kevin ;

Wang, Yifan ;

Greenberg, Roger A. ;

Schwartz, Lauren ;

Johnson, Neil ;

Scharpf, Robert B. ;

Mills, Gordon B. ;

Zhang, Rugang ;

Velculescu, Victor E. ;

Brown, Eric J. ;

Simpkins, Fiona .

NATURE COMMUNICATIONS, 2020, 11 (01)

[27] TGFβ signaling networks in ovarian cancer progression and plasticity [J].

Kumari, Asha ;

Shonibare, Zainab ;

Monavarian, Mehri ;

Arend, Rebecca C. ;

Lee, Nam Y. ;

Inman, Gareth J. ;

Mythreye, Karthikeyan .

CLINICAL & EXPERIMENTAL METASTASIS, 2021, 38 (02) :139-161

[28]

LANGDON SP, 1988, CANCER RES, V48, P6166

[29] TGFβR-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment [J].

Le, Bac Viet ;

Podszywalow-Bartnicka, Paulina ;

Maifrede, Silvia ;

Sullivan-Reed, Katherine ;

Nieborowska-Skorska, Margaret ;

Golovine, Konstantin ;

Yao, Juo-Chin ;

Nejati, Reza ;

Cai, Kathy Q. ;

Caruso, Lisa Beatrice ;

Swatler, Julian ;

Dabrowski, Michal ;

Lian, Zhaorui ;

Valent, Peter ;

Paietta, Elisabeth M. ;

Levine, Ross L. ;

Fernandez, Hugo F. ;

Tallman, Martin S. ;

Litzow, Mark R. ;

Huang, Jian ;

Challen, Grant A. ;

Link, Daniel ;

Tempera, Italo ;

Wasik, Mariusz A. ;

Piwocka, Katarzyna ;

Skorski, Tomasz .

CELL REPORTS, 2020, 33 (01)

[30] ESGO-ESMO-ESP consensus conference recommendations on ovarian cancer: pathology and molecular biology and early, advanced and recurrent disease [J].

Ledermann, J. A. ;

Matias-Guiu, X. ;

Amant, F. ;

Concin, N. ;

Davidson, B. ;

Fotopoulou, C. ;

Gonzalez-Martin, A. ;

Gourley, C. ;

Leary, A. ;

Lorusso, D. ;

Banerjee, S. ;

Chiva, L. ;

Cibula, D. ;

Colombo, N. ;

Croce, S. ;

Eriksson, A. G. ;

Falandry, C. ;

Fischerova, D. ;

Harter, P. ;

Joly, F. ;

Lazaro, C. ;

Lok, C. ;

Mahner, S. ;

Marme, F. ;

Marth, C. ;

McCluggage, W. G. ;

Mcneish, I. A. ;

Morice, P. ;

Nicum, S. ;

Oaknin, A. ;

Perez-Fidalgo, J. A. ;

Pignata, S. ;

Ramirez, P. T. ;

Ray-Coquard, I. ;

Romero, I. ;

Scambia, G. ;

Sehouli, J. ;

Shapira-Frommer, R. ;

Sundar, S. ;

Tan, D. S. P. ;

Taskiran, C. ;

van Driel, W. J. ;

Vergote, I. ;

Planchamp, F. ;

Sessa, C. ;

Fagotti, A. .

ANNALS OF ONCOLOGY, 2024, 35 (03) :248-266

← 1 2 3 4 5 6 7 8 →