IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer

被引：40

作者：

Bley, Nadine ^{[1
]}

Schott, Annekatrin ^{[1
]}

Mueller, Simon ^{[1
]}

Misiak, Danny ^{[1
]}

Lederer, Marcell ^{[1
]}

Fuchs, Tommy ^{[1
]}

Assmann, Chris ^{[1
]}

Glass, Markus ^{[1
]}

Ihling, Christian ^{[2
]}

Sinz, Andrea ^{[2
]}

Pazaitis, Nikolaos ^{[3
]}

Wickenhauser, Claudia ^{[3
]}

Vetter, Martina ^{[4
]}

Ungurs, Olga ^{[4
]}

Strauss, Hans-Georg ^{[4
]}

Thomssen, Christoph ^{[4
]}

Huettelmaier, Stefan ^{[1
]}

机构：

[1] Martin Luther Univ Halle Wittenberg, Inst Mol Med, Fac Med, Sect Mol Cell Biol,Charles Tanford Prot Ctr, D-06120 Halle, Germany

[2] Martin Luther Univ Halle Wittenberg, Inst Pharm, Charles Tanford Prot Ctr, Dept Pharmaceut Chem & Bioanalyt, Halle, Germany

[3] Martin Luther Univ Halle Wittenberg, Fac Med, Inst Pathol, Halle, Germany

[4] Martin Luther Univ Halle Wittenberg, Fac Med, Clin Gynecol, Halle, Germany

来源：

RNA BIOLOGY | 2021年 / 18卷 / 03期

关键词：

IGF2BP1; invasion; SRC; ERK2; resistance; saracatinib; selumetinib; signalling; GRADE SEROUS CARCINOMA; RNA-BINDING PROTEINS; SRC FAMILY KINASES; MESSENGER-RNA; ACQUIRED-RESISTANCE; FALLOPIAN-TUBE; CODING REGION; PHOSPHORYLATION; CATENIN; ACTIVATION;

D O I：

10.1080/15476286.2020.1812894

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Epithelial-to-mesenchymal transition (EMT) is a hallmark of aggressive, mesenchymal-like high-grade serous ovarian carcinoma (HGSOC). The SRC kinase is a key driver of cancer-associated EMT promoting adherens junction (AJ) disassembly by phosphorylation-driven internalization and degradation of AJ proteins. Here, we show that the IGF2 mRNA-binding protein 1 (IGF2BP1) is up-regulated in mesenchymal-like HGSOC and promotes SRC activation by a previously unknown protein-ligand-induced, but RNA-independent mechanism. IGF2BP1-driven invasive growth of ovarian cancer cells essentially relies on the SRC-dependent disassembly of AJs. Concomitantly, IGF2BP1 enhances ERK2 expression in an RNA-binding dependent manner. Together this reveals a post-transcriptional mechanism of interconnected stimulation of SRC/ERK signalling in ovarian cancer cells. The IGF2BP1-SRC/ERK2 axis is targetable by the SRC-inhibitor saracatinib and MEK-inhibitor selumetinib. However, due to IGF2BP1-directed stimulation, only combinatorial treatment effectively overcomes the IGF2BP1-promoted invasive growth in 3D culture conditions as well as intraperitoneal mouse models. In conclusion, we reveal an unexpected role of IGF2BP1 in enhancing SRC/MAPK-driven invasive growth of ovarian cancer cells. This provides a rationale for the therapeutic benefit of combinatorial SRC/MEK inhibition in mesenchymal-like HGSOC.

引用

页码：391 / 403

页数：13

共 52 条

[1] Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary [J].

Ahmed, Ashour Ahmed ;

Etemadmoghadam, Dariush ;

Temple, Jillian ;

Lynch, Andy G. ;

Riad, Mohamed ;

Sharma, Raghwa ;

Stewart, Colin ;

Fereday, Sian ;

Caldas, Carlos ;

DeFazio, Anna ;

Bowtell, David ;

Brenton, James D. .

JOURNAL OF PATHOLOGY, 2010, 221 (01) :49-56

[2] Integrated genomic analyses of ovarian carcinoma [J].

Bell, D. ;

Berchuck, A. ;

Birrer, M. ;

Chien, J. ;

Cramer, D. W. ;

Dao, F. ;

Dhir, R. ;

DiSaia, P. ;

Gabra, H. ;

Glenn, P. ;

Godwin, A. K. ;

Gross, J. ;

Hartmann, L. ;

Huang, M. ;

Huntsman, D. G. ;

Iacocca, M. ;

Imielinski, M. ;

Kalloger, S. ;

Karlan, B. Y. ;

Levine, D. A. ;

Mills, G. B. ;

Morrison, C. ;

Mutch, D. ;

Olvera, N. ;

Orsulic, S. ;

Park, K. ;

Petrelli, N. ;

Rabeno, B. ;

Rader, J. S. ;

Sikic, B. I. ;

Smith-McCune, K. ;

Sood, A. K. ;

Bowtell, D. ;

Penny, R. ;

Testa, J. R. ;

Chang, K. ;

Dinh, H. H. ;

Drummond, J. A. ;

Fowler, G. ;

Gunaratne, P. ;

Hawes, A. C. ;

Kovar, C. L. ;

Lewis, L. R. ;

Morgan, M. B. ;

Newsham, I. F. ;

Santibanez, J. ;

Reid, J. G. ;

Trevino, L. R. ;

Wu, Y. -Q. ;

Wang, M. .

NATURE, 2011, 474 (7353) :609-615

[3] Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs): post-transcriptional drivers of cancer progression? [J].

Bell, Jessica L. ;

Waechter, Kristin ;

Muehleck, Britta ;

Pazaitis, Nikolaos ;

Koehn, Marcel ;

Lederer, Marcell ;

Huettelmaier, Stefan .

CELLULAR AND MOLECULAR LIFE SCIENCES, 2013, 70 (15) :2657-2675

[4] A dynamic reversible RNA N6-methyladenosine modification: current status and perspectives [J].

Bi, Zhen ;

Liu, Youhua ;

Zhao, Yuanling ;

Yao, Yongxi ;

Wu, Ruifan ;

Liu, Qing ;

Wang, Yizhen ;

Wang, Xinxia .

JOURNAL OF CELLULAR PHYSIOLOGY, 2019, 234 (06) :7948-7956

[5] TUMOR EVOLUTION Finding the mutations that drive resistance [J].

Bley, Nadine .

ELIFE, 2020, 9

[6] Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer [J].

Bowtell, David D. ;

Boehm, Steffen ;

Ahmed, Ahmed A. ;

Aspuria, Paul-Joseph ;

Bast, Robert C., Jr. ;

Beral, Valerie ;

Berek, Jonathan S. ;

Birrer, Michael J. ;

Blagden, Sarah ;

Bookman, Michael A. ;

Brenton, James D. ;

Chiappinelli, Katherine B. ;

Martins, Filipe Correia ;

Coukos, George ;

Drapkin, Ronny ;

Edmondson, Richard ;

Fotopoulou, Christina ;

Gabra, Hani ;

Galon, Jerome ;

Gourley, Charlie ;

Heong, Valerie ;

Huntsman, David G. ;

Iwanicki, Marcin ;

Karlan, Beth Y. ;

Kaye, Allyson ;

Lengyel, Ernst ;

Levine, Douglas A. ;

Lu, Karen H. ;

McNeish, Iain A. ;

Menon, Usha ;

Narod, Steven A. ;

Nelson, Brad H. ;

Nephew, Kenneth P. ;

Pharoah, Paul ;

Powell, Daniel J., Jr. ;

Ramos, Pilar ;

Romero, Iris L. ;

Scott, Clare L. ;

Sood, Anil K. ;

Stronach, Euan A. ;

Balkwill, Frances R. .

NATURE REVIEWS CANCER, 2015, 15 (11) :668-679

[7] Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of multidrug resistance 1 [J].

Boyerinas, Benjamin ;

Park, Sun-Mi ;

Murmann, Andrea E. ;

Gwin, Katja ;

Montag, Anton G. ;

Zillhardt, Marion ;

Hua, You-Jia ;

Lengyel, Ernst ;

Peter, Marcus E. .

INTERNATIONAL JOURNAL OF CANCER, 2012, 130 (08) :1787-1797

[8] The oncogenic triangle of HMGA2, LIN28B and IGF2BP1 antagonizes tumor-suppressive actions of the let-7 family [J].

Busch, Bianca ;

Bley, Nadine ;

Mueller, Simon ;

Glass, Markus ;

Misiak, Danny ;

Lederer, Marcell ;

Vetter, Martina ;

Strauss, Hans-Georg ;

Thomssen, Christoph ;

Huettelmaier, Stefan .

NUCLEIC ACIDS RESEARCH, 2016, 44 (08) :3845-3864

[9] Emerging landscape of oncogenic signatures across human cancers [J].

Ciriello, Giovanni ;

Miller, Martin L. ;

Aksoy, Buelent Arman ;

Senbabaoglu, Yasin ;

Schultz, Nikolaus ;

Sander, Chris .

NATURE GENETICS, 2013, 45 (10) :1127-U247

[10] Phospho-regulation of β-catenin adhesion and signaling functions [J].

Daugherty, Rebecca Leadem ;

Gottardi, Cara J. .

PHYSIOLOGY, 2007, 22 (05) :303-309

← 1 2 3 4 5 6 →