COL11A1 is overexpressed in gastric cancer tissues and regulates proliferation, migration and invasion of HGC-27 gastric cancer cells in vitro.

The role of COL11A1 in carcinogenesis is increasingly recognized. However, the biological role and potential mechanisms of COL11A1 in gastric cancer have not been elucidated. In the present study, the COL11A1 mRNA expression in 57 patients with gastric cancer was measured by reverse transcription quantitative PCR (RT-qPCR), and the biological effects of COL11A1 suppression were determined using MTS, monolayer colony formation, flow cytometry and Transwell assays. In addition, the potential molecular mechanisms of COL11A1 in gastric cancer were analyzed by western blotting and cDNA microarray analysis. Compared with matched adjacent non-tumor tissue, COL11A1 mRNA was significantly overexpressed in tumor tissue and was positively related to age, tumor invasion depth, tumor size and lymph node positivity. Moreover, in vitro experiments demonstrated that COL11A1 suppression by short hairpin RNA (shRNA) significantly inhibited the proliferation, migration and invasion of HGC-27 cells and that COL11A1 suppression promoted cell apoptosis, induced G1-phase cell cycle arrest and led to a significant downregulation of cyclin D1 and upregulation of p21 and cleaved caspase-3. In addition, the cDNA microarray analysis of HGC-27 cells with and without COL11A1 suppression indicated that COL11A1 may regulate multiple genes responsible for cell growth and/or invasion, including downregulation of CDK6, TIAM1, ITGB8 and WNT5A and upregulation of RGS2 and NEFL following suppression of COL11A1 expression in HGC-27 cells, validated with RT-qPCR assays. Taken together, our findings demonstrate that COL11A1 might be an oncogene in GC and is a promising therapeutic target in cancer treatment.

[1]  J. R. de los Toyos,et al.  Overexpression of COL11A1 by Cancer-Associated Fibroblasts: Clinical Relevance of a Stromal Marker in Pancreatic Cancer , 2013, PloS one.

[2]  R. Kanwar,et al.  RNAi Mediated Tiam1 Gene Knockdown Inhibits Invasion of Retinoblastoma , 2013, PloS one.

[3]  C. Mathers,et al.  Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012 , 2015, International journal of cancer.

[4]  A. Egloff,et al.  Collagen type XI α1 facilitates head and neck squamous cell cancer growth and invasion , 2013, British Journal of Cancer.

[5]  Wei Zhang,et al.  Differentially expressed genes between primary cancer and paired lymph node metastases predict clinical outcome of node-positive breast cancer patients , 2007, Breast Cancer Research and Treatment.

[6]  A. Lindblom,et al.  Colorectal carcinogenesis is associated with stromal expression of COL11A1 and COL5A2. , 2001, Carcinogenesis.

[7]  T. Hunter,et al.  Cyclins and cancer , 1991, Cell.

[8]  Q. Tong,et al.  Downregulation of XIAP expression induces apoptosis and enhances chemotherapeutic sensitivity in human gastric cancer cells , 2005, Cancer Gene Therapy.

[9]  Y-H Wu,et al.  COL11A1 promotes tumor progression and predicts poor clinical outcome in ovarian cancer , 2014, Oncogene.

[10]  P. Greenwel,et al.  Structural and Functional Analysis of the Promoter of the Human 1(XI) Collagen Gene (*) , 1995, The Journal of Biological Chemistry.

[11]  K. Hess,et al.  Outcome of gastric cancer patients after successful gastrectomy , 2006, Cancer.

[12]  Diana M. Mitrea,et al.  Cell cycle regulation by the intrinsically disordered proteins p 21 and p 27 , 2012 .

[13]  M. Meisler,et al.  Marshall syndrome associated with a splicing defect at the COL11A1 locus. , 1998, American journal of human genetics.

[14]  M. Eshraghi,et al.  Apoptosis and cancer: mutations within caspase genes , 2009, Journal of Medical Genetics.

[15]  Z. Al-Hassnan,et al.  A recessive form of Marshall syndrome is caused by a mutation in the COL11A1 gene , 2012, Journal of Medical Genetics.

[16]  Yuan Zhao,et al.  A Potential Role of Collagens Expression in Distinguishing Between Premalignant and Malignant Lesions in Stomach , 2009, Anatomical record.

[17]  Yonghong Xiao,et al.  Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM , 2010, Proceedings of the National Academy of Sciences.

[18]  P. Yu,et al.  Downregulation of T‑cell lymphoma invasion and metastasis‑inducing factor 1 induces cytoskeletal rearrangement and inhibits the invasive capacity of gastric cancer cells. , 2013, Molecular medicine reports.

[19]  T. Hunter,et al.  Cyclins and cancer II: Cyclin D and CDK inhibitors come of age , 1994, Cell.

[20]  P. Sicinski,et al.  Cell Cycle Progression without Cyclin D-CDK4 and Cyclin D-CDK6 Complexes , 2005, Cell cycle.

[21]  Ying Zhuo,et al.  The role of NEFL in cell growth and invasion in head and neck squamous cell carcinoma cell lines. , 2014, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[22]  G. Serio,et al.  Gene expression analysis of early and advanced gastric cancers , 2007, Oncogene.

[23]  H. Hakonarson,et al.  Common genetic variants in NEFL influence gene expression and neuroblastoma risk. , 2014, Cancer research.

[24]  S. Baek,et al.  RGS2 Suppresses Breast Cancer Cell Growth via a MCPIP1‐Dependent Pathway , 2015, Journal of cellular biochemistry.

[25]  G. Salvesen,et al.  Caspases: opening the boxes and interpreting the arrows , 2002, Cell Death and Differentiation.

[26]  Z. Gatalica,et al.  Epigenetic repression of regulator of G‐protein signaling 2 promotes androgen‐independent prostate cancer cell growth , 2012, International journal of cancer.

[27]  Liviu Badea,et al.  Combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identifies genes specifically overexpressed in tumor epithelia. , 2008, Hepato-gastroenterology.

[28]  Chau-Chyun Sheu,et al.  Great potential of a panel of multiple hMTH1, SPD, ITGA11 and COL11A1 markers for diagnosis of patients with non-small cell lung cancer. , 2006, Oncology reports.

[29]  E. Farber The multistep nature of cancer development. , 1984, Cancer research.

[30]  J. Yates,et al.  A family with Stickler syndrome type 2 has a mutation in the COL11A1 gene resulting in the substitution of glycine 97 by valine in alpha 1 (XI) collagen. , 1996, Human molecular genetics.

[31]  Toshihiro Tanaka,et al.  A functional polymorphism in COL11A1, which encodes the alpha 1 chain of type XI collagen, is associated with susceptibility to lumbar disc herniation. , 2007, American journal of human genetics.

[32]  Diana M. Mitrea,et al.  Cell cycle regulation by the intrinsically disordered proteins p21 and p27. , 2012, Biochemical Society transactions.