Musashi-2 (MSI2) supports TGF-β signaling and inhibits claudins to promote non-small cell lung cancer (NSCLC) metastasis.
Non-small cell lung cancer (NSCLC) has a 5-y survival rate of ∼16%, with most deaths associated with uncontrolled metastasis. We screened for stem cell identity-related genes preferentially expressed in a panel of cell lines with high versus low metastatic potential, derived from NSCLC tumors of Kras(LA1/+);P53(R172HΔG/+) (KP) mice. The Musashi-2 (MSI2) protein, a regulator of mRNA translation, was consistently elevated in metastasis-competent cell lines. MSI2 was overexpressed in 123 human NSCLC tumor specimens versus normal lung, whereas higher expression was associated with disease progression in an independent set of matched normal/primary tumor/lymph node specimens. Depletion of MSI2 in multiple independent metastatic murine and human NSCLC cell lines reduced invasion and metastatic potential, independent of an effect on proliferation. MSI2 depletion significantly induced expression of proteins associated with epithelial identity, including tight junction proteins [claudin 3 (CLDN3), claudin 5 (CLDN5), and claudin 7 (CLDN7)] and down-regulated direct translational targets associated with epithelial-mesenchymal transition, including the TGF-β receptor 1 (TGFβR1), the small mothers against decapentaplegic homolog 3 (SMAD3), and the zinc finger proteins SNAI1 (SNAIL) and SNAI2 (SLUG). Overexpression of TGFβRI reversed the loss of invasion associated with MSI2 depletion, whereas overexpression of CLDN7 inhibited MSI2-dependent invasion. Unexpectedly, MSI2 depletion reduced E-cadherin expression, reflecting a mixed epithelial-mesenchymal phenotype. Based on this work, we propose that MSI2 provides essential support for TGFβR1/SMAD3 signaling and contributes to invasive adenocarcinoma of the lung and may serve as a predictive biomarker of NSCLC aggressiveness.
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111; Department of Medical Oncology, University of New Mexico Cancer Center, Albuquerque, NM 87131;
Alexander E
AE
Kudinov
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111; Kazan Federal University, 420000, Kazan, Russian Federation;
Alexander
0000-0003-2448-5156
A
Deneka
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111;
Anna S
AS
Nikonova
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111; Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA 19111;
Tim N
TN
Beck
Department of Thoracic Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030; Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University School of Medicine, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul, Korea;
Young-Ho
YH
Ahn
Department of Thoracic Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
Xin
X
Liu
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131;
Cathleen F
CF
Martinez
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131;
Fred A
FA
Schultz
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131;
Samuel
S
Reynolds
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111; Genomics Facility, Fox Chase Cancer Center, Philadelphia, PA 19111;
Dong-Hua
DH
Yang
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111; Department of Medical Oncology, University of New Mexico Cancer Center, Albuquerque, NM 87131;
Kathy Q
KQ
Cai
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111;
Khaled M
KM
Yaghmour
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111;
Karmel A
KA
Baker
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111;
Brian L
BL
Egleston
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111; Genomics Facility, Fox Chase Cancer Center, Philadelphia, PA 19111;
Emmanuelle
E
Nicolas
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111; Temple University School of Medicine, Philadelphia, PA 19140;
Adaeze
A
Chikwem
Kazan Federal University, 420000, Kazan, Russian Federation;
Gregory
G
Andrianov
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111;
Shelly
S
Singh
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111.
Hossein
H
Borghaei
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111; Kazan Federal University, 420000, Kazan, Russian Federation;
Ilya G
IG
Serebriiskii
Department of Thoracic Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
Don L
DL
Gibbons
Department of Thoracic Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
Jonathan M
JM
Kurie
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111; Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA 19111; yboumber@gmail.com Erica.Golemis@fccc.edu.
Erica A
EA
Golemis
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111; Department of Medical Oncology, University of New Mexico Cancer Center, Albuquerque, NM 87131; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111 yboumber@gmail.com Erica.Golemis@fccc.edu.
Yanis
Y
Boumber
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D057167:Claudins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D016601:RNA-Binding Proteins / Q000502:physiology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D057167:Claudins; C438151:MSI2 protein, human; D016601:RNA-Binding Proteins; D016212:Transforming Growth Factor beta
MSI2; NSCLC; claudins; lung cancer; metastasis