PMID- 29158795
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200929
IS  - 1837-9664 (Print)
IS  - 1837-9664 (Electronic)
IS  - 1837-9664 (Linking)
VI  - 8
IP  - 16
DP  - 2017
TI  - Mismatch Repair Protein hMLH1, but not hMSH2, Enhances Estrogen-Induced Apoptosis 
      of Colon Cancer Cells.
PG  - 3232-3241
LID - 10.7150/jca.20833 [doi]
AB  - BACKGROUND: Epidemiological studies suggest a protective role of estrogen against 
      colon carcinogenesis; this effect appears to be dependent on mismatch repair 
      (MMR) status. However, the underlying mechanism remains unclear. This study 
      investigated the role of MMR proteins in apoptosis of colon cancer cells in the 
      presence or absence of estrogen. METHODS: Two major MMR proteins, human mutL 
      homolog 1 (hMLH1) and mutS homolog 2 (hMSH2), as well as estrogen receptor-beta 
      (ERbeta), were transiently expressed in either hMLH1-deficient HCT116 cells or 
      hMSH2-deficient LoVo cells. Effects of estradiol on cell viability and apoptosis 
      were assessed. Furthermore, we examined the apoptotic status of epithelial cells 
      in colonic mucosa taken from previous healthy female subjects with menopausal 
      syndrome before and after 6-month hormone replacement therapy (HRT). RESULTS: In 
      hMLH1-deficient HCT116 cells, re-expression of hMLH1 led to a significantly 
      decreased cell viability and increased apoptosis, which were further enhanced by 
      estradiol, including marked increase of activated caspase-3 and caspase-9, as 
      well as Bax and P53. The effect of hMLH1 overexpression in LoVo cells resulted in 
      a similar increase in apoptosis that was greatly stimulated by estradiol. The 
      enhanced apoptosis by hMLH1 and estradiol was further validated by FACS analyses 
      of Annexin V expression. Re-expression of hMSH2 or overexpression of ERbeta in 
      HCT116 cells also enhanced apoptosis; however, the effects were independent of 
      estradiol. Furthermore, studies on healthy menopausal women before and after 
      6-month HRT demonstrated a significant HRT-mediated upregulation of the hMLH1 
      expression, with concomitant elevation of caspase-3 and caspase-9 activation in 
      the colonic mucosa. CONCLUSION: We present the first evidence that hMLH1 and 
      hMSH2 have similar but distinct roles in the apoptosis of colon cancer cells: an 
      increased expression of either one can promote apoptosis, while only the effect 
      of hMLH1 but not hMSH2 is estradiol-dependent. Our data suggest that MMR status 
      should be assessed before hormone replacement therapy or future application of 
      estrogen-based chemoprevention.
FAU - Jin, Peng
AU  - Jin P
AD  - Department of Gastroenterology, PLA Army General Hospital, Beijing 100700, China.
FAU - Wang, De-Zhi
AU  - Wang DZ
AD  - Department of Gastroenterology, PLA Army General Hospital, Beijing 100700, China.
AD  - Johns Hopkins University School of Medicine, Department of Medicine/GI Division, 
      Baltimore, MD21205, USA.
FAU - Lyu, Chen-Xi
AU  - Lyu CX
AD  - Department of Gastroenterology, PLA Army General Hospital, Beijing 100700, China.
FAU - Wang, Ya-Ting
AU  - Wang YT
AD  - Department of Gastroenterology, PLA Army General Hospital, Beijing 100700, China.
FAU - He, Yu-Qi
AU  - He YQ
AD  - Department of Gastroenterology, PLA Army General Hospital, Beijing 100700, China.
FAU - Sheng, Jian-Qiu
AU  - Sheng JQ
AD  - Department of Gastroenterology, PLA Army General Hospital, Beijing 100700, China.
FAU - Li, Xuhang
AU  - Li X
AD  - Johns Hopkins University School of Medicine, Department of Medicine/GI Division, 
      Baltimore, MD21205, USA.
LA  - eng
GR  - P30 DK089502/DK/NIDDK NIH HHS/United States
GR  - R21 DK077064/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20170915
PL  - Australia
TA  - J Cancer
JT  - Journal of Cancer
JID - 101535920
PMC - PMC5665039
OTO - NOTNLM
OT  - Apoptosis.
OT  - Colon cancer
OT  - Estradiol/Estrogen
OT  - Mismatch repair (MMR)
OT  - hMLH1
OT  - hMSH2
COIS- Competing Interests: The authors have declared that no competing interest exists. 
      The manufacturers were not involved in either the design of the study or the 
      analysis of the data.
EDAT- 2017/11/22 06:00
MHDA- 2017/11/22 06:01
PMCR- 2017/01/01
CRDT- 2017/11/22 06:00
PHST- 2017/05/02 00:00 [received]
PHST- 2017/08/25 00:00 [accepted]
PHST- 2017/11/22 06:00 [entrez]
PHST- 2017/11/22 06:00 [pubmed]
PHST- 2017/11/22 06:01 [medline]
PHST- 2017/01/01 00:00 [pmc-release]
AID - jcav08p3232 [pii]
AID - 10.7150/jca.20833 [doi]
PST - epublish
SO  - J Cancer. 2017 Sep 15;8(16):3232-3241. doi: 10.7150/jca.20833. eCollection 2017.