例如:"lncRNA", "apoptosis", "WRKY"

DNA damage signalling as an anti-cancer barrier in gastric intestinal metaplasia.

Gut. 2020 Oct;69(10):1738-1749. Epub 2020 Jan 14
Vaidehi Krishnan 1 , Debbie Xiu En Lim 2 , Phuong Mai Hoang 2 , Supriya Srivastava 3 , Junichi Matsuo 2 , Kie Kyon Huang 1 , Feng Zhu 3 , Khek Yu Ho 4 , Jimmy Bok Yan So 5 , Christopher Khor 6 , Stephen Tsao 7 , Ming Teh 8 , Kwong Ming Fock 9 , Tiing Leong Ang 9 , Anand D Jeyasekharan 2 , Patrick Tan 5 , Khay-Guan Yeoh 5 , Yoshiaki Ito 5
Vaidehi Krishnan 1 , Debbie Xiu En Lim 2 , Phuong Mai Hoang 2 , Supriya Srivastava 3 , Junichi Matsuo 2 , Kie Kyon Huang 1 , Feng Zhu 3 , Khek Yu Ho 4 , Jimmy Bok Yan So 5 , Christopher Khor 6 , Stephen Tsao 7 , Ming Teh 8 , Kwong Ming Fock 9 , Tiing Leong Ang 9 , Anand D Jeyasekharan 2 , Patrick Tan 5 , Khay-Guan Yeoh 5 , Yoshiaki Ito 5
+ et al

[No authors listed]

Author information
  • 1 Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
  • 2 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • 3 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • 4 Department of Gastroenterology and Hepatology, National University Health System, Singapore.
  • 5 Singapore Gastric Cancer Consortium, Singapore.
  • 6 Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore.
  • 7 Department of Gastroenterology and Hepatology, Tan Tock Seng Hospital, Singapore.
  • 8 Department of Pathology, National University of Singapore, Singapore.
  • 9 Department of Gastroenterology, Changi General Hospital, Singapore.

摘要


OBJECTIVE:Intestinal metaplasia (IM) is a premalignant stage that poses a greater risk for subsequent gastric cancer (GC). However, factors regulating IM to GC progression remain unclear. Previously, activated DNA damage response (DDR) signalling factors were shown to engage tumour-suppressive networks in premalignant lesions. Here, we interrogate the relationship of DDR signalling to mutational accumulation in IM lesions. DESIGN:IM biopsies were procured from the gastric cancer epidemiology programme, an endoscopic surveillance programme where biopsies have been subjected to (epi)genomic characterisation. IM samples were classified as genome-stable or genome-unstable based on their mutational burden/somatic copy-number alteration (CNA) profiles. Samples were probed for DDR signalling and cell proliferation, using the markers γH2AX and MCM2, respectively. The expression of the gastric stem cell marker, CD44v9, was also assessed. Tissue microarrays representing the GC progression spectrum were included. RESULTS:MCM2-positivity increased during GC progression, while γH2AX-positivity showed modest increase from normal to gastritis and IM stages, with further increase in GC. γH2AX levels correlated with the extent of chronic inflammation. Interestingly, genome-stable IM lesions had higher γH2AX levels underscoring a protective anti-cancer role for DDR signalling. In contrast, genome-unstable IM lesions with higher mutational burden/CNAs had lower γH2AX levels, elevated CD44v9 expression and modest promoter hypermethylation of DNA repair genes WRN, MLH1 and RAD52. CONCLUSIONS:Our data suggest that IM lesions with active DDR will likely experience a longer latency at the premalignant state until additional hits that override DDR signalling clonally expand and promote progression. These observations provide insights on the factors governing IM progression.

KEYWORDS: DNA damage, gastric cancer, gastric metaplasia