Mismatch Repair Protein hMLH1, but not hMSH2, Enhances Estrogen-Induced Apoptosis of Colon Cancer Cells.
Mismatch Repair Protein hMLH1, but not hMSH2, Enhances Estrogen-Induced Apoptosis of Colon Cancer Cells.
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DOI：
10.7150/jca.20833
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发表时间：
2017
影响因子：
3.9
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Jin P;Wang DZ;Lyu CX;Wang YT;He YQ;Sheng JQ;Li X
背景资料：流行病学研究表明，雌激素对结肠癌的保护作用，这种作用似乎是依赖于错配修复（MMR）的状态。然而，其潜在机制仍不清楚。本研究探讨了在有或无雌激素的情况下，MMR蛋白在结肠癌细胞凋亡中的作用。研究方法：两种主要的MMR蛋白，人mutL同源物1（hMLH 1）和mutS同源物2（hMSH 2），以及雌激素受体β（ERβ），在hMLH 1缺陷的HCT 116细胞或hMSH 2缺陷的LoVo细胞中瞬时表达。评价雌二醇对细胞活力和凋亡的影响。此外，我们研究了结肠粘膜上皮细胞的凋亡状态，从以前的健康女性受试者绝经综合征之前和之后6个月的激素替代治疗（HRT）。结果如下：在hMLH 1缺陷的HCT 116细胞中，hMLH 1的重新表达导致细胞活力显著降低和凋亡增加，雌二醇进一步增强，包括活化的caspase-3和caspase-9，以及Bax和P53的显著增加。hMLH 1过表达在LoVo细胞中的作用导致了类似的凋亡增加，这在很大程度上受到雌二醇的刺激。通过Annexin V表达的FACS分析进一步验证了hMLH 1和雌二醇增强的凋亡。HCT 116细胞中hMSH 2的再表达或ERβ的过表达也促进了细胞凋亡;然而，这种作用不依赖于雌二醇。此外，对健康绝经期妇女的研究表明，6个月的HRT之前和之后的显着HRT介导的hMLH 1的表达上调，伴随着升高的caspase-3和caspase-9的激活在结肠粘膜。结论：我们提出的第一个证据表明，hMLH 1和hMSH 2在结肠癌细胞的凋亡中具有相似但不同的作用：任何一个的表达增加都可以促进细胞凋亡，而只有hMLH 1而不是hMSH 2的作用是雌二醇依赖性的。我们的数据表明，MMR状态应评估激素替代治疗或未来应用雌激素为基础的化学预防。
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-β (ERβ), 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 ERβ 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.
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影响因子：
6.4
作者：
Giroux, Veronique;Lemay, Frederic;Carrier, Julie C.
通讯作者：
Carrier, Julie C.
影响因子：
--
作者：
Edvardsson, Karin;Stroem, Anders;Williams, Cecilia
通讯作者：
Williams, Cecilia
影响因子：
1.6
作者：
Elbanna, Hosam Ghazy;Ebrahim, Mohamed Awad;Hashim, Maha Abo
通讯作者：
Hashim, Maha Abo
影响因子：
1.9
作者：
Barone, Michele;Scavo, Maria Principia;Di Leo, Alfredo
通讯作者：
Di Leo, Alfredo
DOI：
10.1073/pnas.1015541107
发表时间：
2010-12-07
影响因子：
11.1
作者：
Valeri, Nicola;Gasparini, Pierluigi;Croce, Carlo M.
通讯作者：
Croce, Carlo M.