Long noncoding RNA cancer susceptibility candidate 2 suppresses papillary thyroid carcinoma growth by inactivating the AKT/ERK1/2 signaling pathway

J Cell Biochem. 2019 Jun;120(6):10380-10390. doi: 10.1002/jcb.28322. Epub 2019 Jan 4.

Abstract

Objectives: Cancer susceptibility candidate 2 (CASC2) and long noncoding RNA (lncRNA) have been identified as a tumor suppressor in colorectal, lung, renal, and stomach cancer as well as in patient gliomas, but the function of CASC2 in papillary thyroid carcinoma (PTC) is not yet clear. The present study aimed to explore the effects of CASC2 in PTC.

Methods: The CASC2 expression was measured in PTC samples and normal tissues by using quantitative real-time polymerase chain reaction. The lentiviral vectors were used to establish CASC2 overexpression models in PTC cell lines to determine the effects of CASC2 on cell proliferation, apoptosis, migration, and invasion. A tumor xenograft animal model was used to examine the functions of overexpression CASC2.

Results: CASC2 expression was significantly decreased in PTC tumor tissues than adjacent normal tissues. CASC2 downregulation in PTC tissues significantly correlated with the tumor size, the presence of multifocal lesions, and the advanced pathological stage. CASC2 overexpression suppressed the cell proliferation and promoted apoptosis in PTC cell lines and CASC2 overexpression resulted in the inactivation of protein kinase B (PKB/AKT) and extracellular signal-regulated kinases (ERK1/2). The regulatory effects of CASC2 on PTC cell biological behavior were further enhanced by mitogen-activated protein kinase kinase (MEK) inhibitor U0126 or AKT1/2/3 inhibitor MK-2206 2HCl. CASC2 overexpression suppressed tumor growth in PTC cells in xenograft mouse models.

Conclusion: Our results indicated that CASC2 significantly suppressed tumorigenesis in PTC and CASC2 may serve as a novel prognostic marker or therapeutic target.

Keywords: cancer susceptibility candidate 2 (CASC2); long noncoding RNA (lncRNA); migration; papillary thyroid carcinoma (PTC); proliferation.

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Cell Movement
  • Cell Proliferation
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Prognosis
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Thyroid Cancer, Papillary / genetics
  • Thyroid Cancer, Papillary / metabolism
  • Thyroid Cancer, Papillary / pathology*
  • Thyroid Neoplasms / genetics
  • Thyroid Neoplasms / metabolism
  • Thyroid Neoplasms / pathology
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • Tumor Suppressor Proteins
  • long non-coding RNA CASC2, human
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • MAPK1 protein, human
  • MAPK3 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3