Prognostic value of the cancer oncogene Kelch-like 6 in gastric cancer

Br J Surg. 2017 Dec;104(13):1847-1856. doi: 10.1002/bjs.10628. Epub 2017 Oct 17.


Background: Kelch-like 6 (KLHL6) is a cancer oncogene previously associated with specific human cancers, such as chronic lymphocytic leukaemia. Here, the mechanisms of KLHL6 function were explored in gastric cancer (GC) cells, in an in vivo experimental tumour model, and the prognostic value of KLHL6 analysis in GC tissue evaluated in a cohort of patients with GC.

Methods: Associations between clinicopathological and survival data and KLHL6 expression in GC tissues were analysed. The effects of downregulation of KLHL6 in GC cells was investigated using proliferation, invasion, apoptosis and lymphangiogenesis assays, and analysis of tumour growth in an in vivo experimental model.

Results: KLHL6 was upregulated in 43 per cent of GC tissues compared with 5 per cent of paired non-tumour tissues from 84 patients. KLHL6 protein expression in GC tissues was much higher than that in atrophic gastritis, intestinal metaplasia and dysplasia tissues from benign gastric disease samples. KLHL6 expression was positively related to the intestinal Laurén classification in GC tissues. Downregulated expression of KLHL6 in MGC-803 GC cells reduced colony formation, proliferation, viability, migration and invasion, enhanced apoptosis and inhibited the cell cycle in the G1 phase. Downregulated expression of KLHL6 also suppressed tumour growth in mice. Furthermore, downregulated expression of KLHL6 mRNA reduced the expression of nuclear-associated antigen Ki-67, vascular endothelial growth factor C, hepatocyte growth factor and matrix metalloproteinase 2 in vitro, and KLHL6 protein in tumour tissue of mice.

Conclusion: Abnormal expression of the KLHL6 oncogene promoted GC progression in vitro and in vivo, and its expression level in tumour tissue was found to be of prognostic value.

MeSH terms

  • Animals
  • Apoptosis
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Down-Regulation
  • Female
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Ki-67 Antigen / metabolism
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Mice, Nude
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasms, Experimental
  • Prognosis
  • RNA, Messenger / metabolism
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / mortality*
  • Stomach Neoplasms / pathology
  • Up-Regulation
  • Vascular Endothelial Growth Factor C / metabolism


  • Carrier Proteins
  • KLHL6 protein, human
  • Ki-67 Antigen
  • RNA, Messenger
  • Vascular Endothelial Growth Factor C
  • Hepatocyte Growth Factor
  • Matrix Metalloproteinase 2