Loss of the vitamin D receptor in human breast and prostate cancers strongly induces cell apoptosis through downregulation of Wnt/β-catenin signaling

Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D, 1,25-dihydroxy-vitamin D [1,25（OH）2D] are mediated through binding to the vitamin D receptor （VDR）. Here, we report on the unexpected finding that stable knockdown of VDR expression in the human breast and prostate cancer cell lines, MDA-MB-231 and PC3, strongly induces cell apoptosis and inhibits cell proliferation in vitro. Implantation of these VDR knockdown cells into the mammary fat pad （MDA-MB-231）, subcutaneously （PC3） or intra-tibially （both cell lines） in immune-incompetent nude mice resulted in reduced tumor growth associated with increased apoptosis and reduced cell proliferation compared with controls. These growth-retarding effects of VDR knockdown occur in the presence and absence of vitamin D and are independent of whether cells were grown in bone or soft tissues. Transcriptome analysis of VDR knockdown and non-target control cell lines demonstrated that loss of the VDR was associated with significant attenuation in the Wnt/0-catenin signaling pathway. In particular, cytoplasmic and nuclear β-catenin protein levels were reduced with a corresponding downregulation of downstream genes such as Axin2, Cyclin D1, interleukin-6 （IL-6）, and IL-8. Stabilization of 0-catenin using the GSK-3β inhibitor BIO partly reversed the growth-retarding effects of VDR knockdown. Our results indicate that the unliganded VDR possesses hitherto unknown functions to promote breast and prostate cancer growth, which appear to be operational not only within but also outside the bone environment. These novel functions contrast with the known anti-proliferative nuclear actions of the liganded VDR and may represent targets for new diagnostic and therapeutic approaches in breast and prostate cancer.

Therapeutic effect of Qinghuayin(清化饮)against chronic atrophic gastritis through the inhibition of toll or interleukin-1 receptor domain-containing adaptor inducing interferon-β signaling pathway

OBJECTIVE:To examine the efficacy of Qinghuayin(清化饮,QHY)in rat chronic atrophic gastritis(CAG)models and explored the molecular mechanism of QHY in treating CAG.METHODS:In total,65 Wistar rats were randomly divided into the control(n=10)and CAG groups(n=55).CAG model rats were further divided into five groups:model(n=10),vitacoenzyme(n=10),low-dose QHY(n=10),medium-dose QHY(n=10),and high-dose QHY groups(n=10).We analyzed histopathological changes using hematoxylin and eosin staining and measured interleukin(IL)-6 and IL-8 levels in serum using enzyme-linked immunosorbent assay(ELISA)(Boster Bio,Pleasanton,USA).In addition,gastrin(GAS),pepsinogen I(PGI),and PGII expressions were evaluated using ELISA.The protein and m RNA expression of toll-like receptor 4(TLR4)and toll or interleukin-1 receptor domaincontaining adaptor inducing interferon-β(TRIF)was detected by Western blotting and quantitative reverse transcription-polymerase chain reaction,respectively.RESULTS:Our results revealed that histopathological changes in CAG model rates could be restored by low-,medium-,and high-dose QHY.The changes in GAS and PGI/II expression demonstrated that QHY improved CAG.Serum IL-6 and IL-levels were decreased by QHY administration.TLR4 and TRIF were upregulated at the m RNA and protein levels in the model group but downregulated by QHY administration.CONCLUSION:We concluded that QHY could effectively improve the histopathological changes of the gastric mucosa induced by CAG in rats.The therapeutic mechanism of QHY may be related to inhibition of the inflammatory factors IL-6 and IL-8 and suppression of TLR4/TRIF m RNA and protein expression.

Study on Relationship between Ovulation Inducing Effect of Drug-Acupuncture and Endometrial Contents of Estradiol Receptor and Progesterone Receptor

Objective: To study the effect of Chineseherbal medicine for replenishing Kidney combined with acupuncture in treating anovulationand infertility, and the relationship betweenits ovulation inducing effect and endometrialcontents of estradiol receptor (ER) and progesterone receptor (PR). Methods: Twentynine cases were treated with replenishing Kidney drugs combined with acupuncture for 1～3months. Patients' ER and PR were measuredby immunohistochemical method. And pa- tients were classified according to PR contentinto PR positive group and mild PR positivegroup. Results: Fifteen cases of PR positivegroup, completed treatment for 45 cycles, among them, 40 cycles showed ovulation, theovulation rate being 88. 89 %. Ten in 14 cases, who complicated with infertility, becamepregnant, the pregnant rate being 71. 43%.While in 11 cases of Ph mild positive group, 9complicated with in fertility, completed treatment for 33 cycle, 10 cycles showed ovulation(30. 30 % ), and pregnant rate 22. 22 % (2/9). The difference between the two groupswas significant (P < 0. 01 ). Conclusion: Thereplenishing Kidney drugs combined withacupuncture treatment could result a good effect in treating infertility due to anovulation,especially on those with high endometrial PRcontent.