HOXC10 up-regulation contributes to human thyroid cancer and indicates poor survival outcome.

HOX genes have been well described as important players in development and morphogenesis, and more recently, in carcinogenesis. The role and clinical implication of homeodomain-containing gene 10 (HOXC10) in human thyroid cancer is poorly understood. Real-time PCR and bioinformatics analysis were used to detect the expression of HOXC10 in normal and human thyroid cancer samples from Shanghai General Hospital (also known as Shanghai First People's Hospital) and the TCGA dataset. The survival time of patients with human thyroid cancer was also detected. Cell Count Kit-8 (CCK8) analysis was used to detect cell proliferation, and the cell cycle was assessed by flow cytometry. Migration and invasion were detected by transwell analysis. Gene set enrichment analysis (GSEA) was used to explore the correlation of HOXC10 with signaling pathways. Real-time PCR and Western blot analysis were used to detect the expression of signaling pathway related genes in human thyroid cancer cells. HOXC10 expression in Shanghai General Hospital and the TCGA dataset revealed a significant increase in human thyroid cancer tissues and its expression was positively correlated with the advanced age, poor pathologic stage, and poor prognosis. HOXC10 knockdown by shRNA conferred cell cycle blocking and inhibition of migration and invasion. GSEA in the TCGA datasets revealed that HOXC10 expression was positively correlated with cytokine-cytokine receptor interaction and chemokine signaling pathways. Our data suggest that inhibition of HOXC10 may be a therapeutic strategy for human thyroid cancer treatment. This study investigates the role and clinical implication of HOXC10 in human thyroid cancer.

[1]  C. Hill,et al.  Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. , 2006, Cytokine & growth factor reviews.

[2]  Jian Chen,et al.  Epigenetic Reprogramming of HOXC10 in Endocrine-Resistant Breast Cancer , 2014, Science Translational Medicine.

[3]  David Baltimore,et al.  A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B all , 1990, Cell.

[4]  M. Sporn,et al.  Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[5]  S. Qiu,et al.  CXCL5 contributes to tumor metastasis and recurrence of intrahepatic cholangiocarcinoma by recruiting infiltrative intratumoral neutrophils. , 2014, Carcinogenesis.

[6]  A. Mercurio,et al.  Deoxyribonucleic-binding homeobox proteins are augmented in human cancer. , 1990, Laboratory investigation; a journal of technical methods and pathology.

[7]  Helen Sadik.  Investigating the Role of HOXC10 as a Mediator of Metastasis in Breast Cancer , 2014 .

[8]  S. Christmas,et al.  Interleukin-8 as an autocrine growth factor for human colon carcinoma cells in vitro. , 2000, Cytokine.

[9]  M. Grütter,et al.  The crystal structure of TGF‐β3 and comparison to TGF‐β2: Implications for receptor binding , 1996, Protein science : a publication of the Protein Society.

[10]  M. Kagnoff,et al.  Chemokine receptor expression by human intestinal epithelial cells. , 1999, Gastroenterology.

[11]  Allan Balmain,et al.  TGF-β signaling in tumor suppression and cancer progression , 2001, Nature Genetics.

[12]  D. Schadendorf,et al.  IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. , 1993, Journal of immunology.

[13]  E. Diamandis,et al.  Proteomic signatures of angiogenesis in androgen‐independent prostate cancer , 2014, The Prostate.

[14]  R. Derynck,et al.  Effects of MGSA/GRO alpha on melanocyte transformation. , 1991, Oncogene.

[15]  E. Boncinelli,et al.  Expression of homeobox-containing genes in primary and metastatic colorectal cancer. , 1993, European journal of cancer.

[16]  Y. Hasegawa,et al.  EGFR-TKI resistance due to BIM polymorphism can be circumvented in combination with HDAC inhibition. , 2013, Cancer research.

[17]  J. Massagué,et al.  The transforming growth factor-β system, a complex pattern of cross-reactive ligands and receptors , 1987, Cell.

[18]  S. Mandal,et al.  HOXC10 is overexpressed in breast cancer and transcriptionally regulated by estrogen via involvement of histone methylases MLL3 and MLL4. , 2012, Journal of molecular endocrinology.

[19]  A. Balmain,et al.  TGF-beta signaling in tumor suppression and cancer progression. , 2001, Nature genetics.

[20]  A. Zlotnik,et al.  Chemokines: a new classification system and their role in immunity. , 2000, Immunity.

[21]  P. Dhawan,et al.  A novel NF-kappa B-inducing kinase-MAPK signaling pathway up-regulates NF-kappa B activity in melanoma cells. , 2002, The Journal of biological chemistry.

[22]  L. Sachs,et al.  DNA rearrangement of a homeobox gene in myeloid leukaemic cells. , 1988, The EMBO journal.

[23]  M. Kagnoff,et al.  A distinct array of proinflammatory cytokines is expressed in human colon epithelial cells in response to bacterial invasion. , 1995, The Journal of clinical investigation.

[24]  Zhuang Liu,et al.  Drug delivery with carbon nanotubes for in vivo cancer treatment , 2008, 0808.2070.

[25]  S. Korsmeyer,et al.  Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia. , 1991, Science.

[26]  M. Iannettoni,et al.  Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. , 1998, The Journal of clinical investigation.

[27]  P. Bunn,et al.  Altered HOX and WNT7A expression in human lung cancer. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[28]  A. Watanabe,et al.  Effect of interleukin-8 on production of tumor-associated substances and autocrine growth of human liver and pancreatic cancer cells , 1998, Cancer Immunology, Immunotherapy.

[29]  F. Balkwill.  Cancer and the chemokine network , 2004, Nature Reviews Cancer.

[30]  Sung-Liang Yu,et al.  Anti-invasive gene expression profile of curcumin in lung adenocarcinoma based on a high throughput microarray analysis. , 2004, Molecular pharmacology.

[31]  J. Massagué.  The transforming growth factors , 1985 .

[32]  L. Cornelius,et al.  The role of chemokines in melanoma tumor growth and metastasis. , 2002, The Journal of investigative dermatology.

[33]  E. Boncinelli,et al.  HOX gene expression in normal and neoplastic human kidney , 1992, International journal of cancer.

[34]  William McGinnis,et al.  Homeobox genes and axial patterning , 1992, Cell.

[35]  Rakesh Nagarajan,et al.  High throughput digital quantification of mRNA abundance in primary human acute myeloid leukemia samples. , 2009, The Journal of clinical investigation.

[36]  M. Burdick,et al.  CXC chemokines in angiogenesis relevant to chronic fibroproliferation. , 2005, Current drug targets. Inflammation and allergy.

[37]  T. Wang,et al.  Identification of Gastric Cancer Stem Cells Using the Cell Surface Marker CD44 , 2009, Stem cells.

[38]  M. Giacca,et al.  Selection of homeotic proteins for binding to a human DNA replication origin. , 2000, Journal of molecular biology.

[39]  M. Giacca,et al.  Early mitotic degradation of the homeoprotein HOXC10 is potentially linked to cell cycle progression , 2003, The EMBO journal.

[40]  A. Stadnyk,et al.  The functional significance behind expressing two IL–8 receptor types on PMN , 2009, Journal of leukocyte biology.

[41]  Jing-Gung Chung,et al.  Sodium ascorbate inhibits growth via the induction of cell cycle arrest and apoptosis in human malignant melanoma A375.S2 cells , 2006, Melanoma research.

[42]  Jill P. Mesirov,et al.  GSEA-P: a desktop application for Gene Set Enrichment Analysis , 2007, Bioinform..

[43]  R. Strieter,et al.  CXC chemokines in angiogenesis of cancer. , 2004, Seminars in cancer biology.

[44]  Hung Li,et al.  Expression of homeobox genes in cervical cancer. , 2002, Gynecologic oncology.

[45]  V. Castronovo,et al.  HOXC5 and HOXC8 expression are selectively turned on in human cervical cancer cells compared to normal keratinocytes. , 1999, Biochemical and biophysical research communications.

[46]  P. Dhawan,et al.  Correction: A Novel NF-κB-inducing Kinase-MAPK Signaling Pathway Up-regulates NF-κB Activity in Melanoma Cells , 2001, The Journal of Biological Chemistry.