PARD3 Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion.

Correct apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the cell polarity regulator PARD3 to the development of lung squamous cell carcinomas (LSCC). Tumor-specific PARD3 alterations were found in 8% of LSCCs examined, placing PARD3 among the most common tumor suppressor genes in this malignancy. Most PAR3-mutant proteins exhibited a relative reduction in the ability to mediate formation of tight junctions and actin-based protrusions, bind atypical protein kinase C, activate RAC1, and activate STAT3 at cell confluence. Thus, PARD3 alterations prevented the formation of contacts between neighboring cells and the subsequent downstream signaling. Notably, reconstituting PAR3 activity in vivo reduced tumor-invasive and metastatic properties. Our findings define PARD3 as a recurrently inactivated cell polarity regulator in LSCC that affects tumor aggressiveness and metastasis.

[1]  J. Turkson,et al.  The R(h)oads to Stat3: Stat3 activation by the Rho GTPases. , 2011, Experimental cell research.

[2]  John G. Collard,et al.  Tumor type-dependent function of the par3 polarity protein in skin tumorigenesis. , 2012, Cancer cell.

[3]  Chau-Zen Wang,et al.  A discoidin domain receptor 1/SHP-2 signaling complex inhibits alpha2beta1-integrin-mediated signal transducers and activators of transcription 1/3 activation and cell migration. , 2006, Molecular biology of the cell.

[4]  J. Benítez,et al.  Gene amplification of the transcription factor DP1 and CTNND1 in human lung cancer , 2010, The Journal of pathology.

[5]  R. Hoffman,et al.  Site-specific chemosensitivity of human small-cell lung carcinoma growing orthotopically compared to subcutaneously in SCID mice: the importance of orthotopic models to obtain relevant drug evaluation data. , 1993, Anticancer research.

[6]  A. Knudson.  Mutation and cancer: statistical study of retinoblastoma. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[7]  H. Vikis,et al.  Regulation of STAT3 by direct binding to the Rac1 GTPase. , 2000, Science.

[8]  Brian H. Dunford-Shore,et al.  Somatic mutations affect key pathways in lung adenocarcinoma , 2008, Nature.

[9]  Jun Yokota,et al.  A gene‐alteration profile of human lung cancer cell lines , 2009, Human mutation.

[10]  M. Esteller,et al.  Modeling lung cancer evolution and preclinical response by orthotopic mouse allografts. , 2014, Cancer research.

[11]  John G. Collard,et al.  The Par-Tiam1 Complex Controls Persistent Migration by Stabilizing Microtubule-Dependent Front-Rear Polarity , 2007, Current Biology.

[12]  M. Sanchez-Cespedes.  A role for LKB1 gene in human cancer beyond the Peutz–Jeghers syndrome , 2007, Oncogene.

[13]  E. Sahai,et al.  Collective cell migration requires suppression of actomyosin at cell-cell contacts mediated by DDR1 and the cell polarity regulators Par3 and Par6 , 2010, Nature Cell Biology.

[14]  I. Petersen,et al.  Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer , 2010, Science Translational Medicine.

[15]  Jun Yokota,et al.  Frequent BRG1/SMARCA4–inactivating mutations in human lung cancer cell lines , 2008, Human mutation.

[16]  David Sidransky,et al.  Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. , 2002, Cancer research.

[17]  A. Regev,et al.  SOX2 Is an Amplified Lineage Survival Oncogene in Lung and Esophageal Squamous Cell Carcinomas , 2009, Nature Genetics.

[18]  M. Sanchez-Cespedes.  Lung cancer biology: a genetic and genomic perspective , 2009, Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico.

[19]  M. Edwards,et al.  The Airway Epithelium: Soldier in the Fight against Respiratory Viruses , 2011, Clinical Microbiology Reviews.

[20]  M. Zeitz,et al.  Cell polarity-determining proteins Par-3 and PP-1 are involved in epithelial tight junction defects in coeliac disease , 2011, Gut.

[21]  References , 1971 .

[22]  J. Fagin,et al.  STAT3 negatively regulates thyroid tumorigenesis , 2012, Proceedings of the National Academy of Sciences.

[23]  I. M. Jones,et al.  Many amino acid substitution variants identified in DNA repair genes during human population screenings are predicted to impact protein function. , 2004, Genomics.

[24]  J. Jen,et al.  Distinguishing second primary tumors from lung metastases in patients with head and neck squamous cell carcinoma. , 1998, Journal of the National Cancer Institute.

[25]  T. Mäkelä,et al.  Molecular mechanisms of tumor suppression by LKB1 , 2011, FEBS letters.

[26]  M. Rivera,et al.  A genome-wide screen for microdeletions reveals disruption of polarity complex genes in diverse human cancers. , 2010, Cancer research.

[27]  B. Halmos,et al.  PIAS3 activates the intrinsic apoptotic pathway in non‐small cell lung cancer cells independent of p53 status , 2014, International journal of cancer.

[28]  M. Meyerson,et al.  Mutations in the DDR 2 Kinase Gene identify a Novel therapeutic target in squamous cell lung cancer , 2011 .

[29]  M. Perez-Moreno,et al.  Epithelial cell polarity, stem cells and cancer , 2011, Nature Reviews Cancer.

[30]  I. Macara,et al.  Par-3 controls tight junction assembly through the Rac exchange factor Tiam1 , 2005, Nature Cell Biology.

[31]  T. Pawson,et al.  A mammalian PAR-3–PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity , 2000, Nature Cell Biology.

[32]  J. Grandis,et al.  Activation of Stat3 by cell confluence reveals negative regulation of Stat3 by cdk2 , 2003, Oncogene.

[33]  M. Meyerson,et al.  Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. , 2011, Cancer discovery.

[34]  K. Kaibuchi,et al.  Rho-kinase phosphorylates PAR-3 and disrupts PAR complex formation. , 2008, Developmental cell.

[35]  A. Suzuki,et al.  Self-association of PAR-3-mediated by the Conserved N-terminal Domain Contributes to the Development of Epithelial Tight Junctions* , 2003, Journal of Biological Chemistry.

[36]  Ulrich Tepass,et al.  Novel insights into epithelial polarity proteins in Drosophila. , 2011, Trends in cell biology.

[37]  S. Mustjoki,et al.  Somatic STAT3 mutations in large granular lymphocytic leukemia. , 2012, The New England journal of medicine.

[38]  Marissa E. Nolan,et al.  Par complex in cancer: a regulator of normal cell polarity joins the dark side , 2008, Oncogene.

[39]  J. Montalbano,et al.  Loss of the Par3 polarity protein promotes breast tumorigenesis and metastasis. , 2012, Cancer cell.

[40]  A. Goldberg,et al.  Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules , 1994, Cell.

[41]  J. Yokota,et al.  Association of CDKN2A (p16)/CDKN2B (p15) alterations and homozygous chromosome arm 9p deletions in human lung carcinoma , 1998, Genes, chromosomes & cancer.

[42]  R. Benton,et al.  A Conserved Oligomerization Domain in Drosophila Bazooka/PAR-3 Is Important for Apical Localization and Epithelial Polarity , 2003, Current Biology.

[43]  M. Takeichi,et al.  Willin and Par3 cooperatively regulate epithelial apical constriction through aPKC-mediated ROCK phosphorylation , 2011, Nature Cell Biology.

[44]  J. Turkson,et al.  Cell-to-cell adhesion modulates Stat3 activity in normal and breast carcinoma cells , 2004, Oncogene.

[45]  D. Morton,et al.  Identification of genes required for cytoplasmic localization in early C. elegans embryos , 1988, Cell.

[46]  Steven J. M. Jones,et al.  Comprehensive genomic characterization of squamous cell lung cancers , 2012, Nature.

[47]  B. Baum,et al.  Polarity proteins and Rho GTPases cooperate to spatially organise epithelial actin-based protrusions , 2010, Journal of Cell Science.

[48]  Bob Goldstein,et al.  The PAR proteins: fundamental players in animal cell polarization. , 2007, Developmental cell.