Tumour-derived exosomes under hypoxic conditions contain informative miRNAs involved in the interaction of cancer and para-carcinoma cells, thus contributing to tissue remodelling of the tumour microenvironment (TME). Exosomes isolated from hypoxic papillary thyroid cancer cells, BCPAP cells and KTC-1 cells enhanced the angiogenesis of human umbilical vein endothelial cells (HUVECs) compared with exosomes isolated from normal thyroid follicular cell line (Nthy-ori-3-1), normoxic BCPAP or KTC-1 cells both in vitro and in vivo. miR-21-5p was significantly upregulated in exosomes from papillary thyroid cancer BCPAP cells under hypoxic conditions, while the exosomes isolated from hypoxic BCPAP cells with knockdown of miR-21-5p attenuated the promoting effect of angiogenesis. In addition, our experiment revealed that miR-21-5p directly targeted and suppressed TGFBI and COL4A1, thereby increasing endothelial tube formation. Furthermore, elevated levels of exosomal miR-21-5p are found in the sera of papillary thyroid cancer patients, which promote the angiogenesis of HUVECs. Taken together, our study reveals the cell interaction between hypoxic papillary thyroid cancer cells and endothelial cells, elucidating a new mechanism by which hypoxic papillary thyroid cancer cells increase angiogenesis via exosomal miR-21-5p/TGFBI and miR-21-5p/COL4A1 regulatory pathway.
Feng Wu, Fuxingzi Li, Xiao Lin, Feng Xu, Rong-Rong Cui, Jia-Yu Zhong, Ting Zhu, Su-Kang Shan, Xiao-Bo Liao, Ling-Qing Yuan and Zhao-Hui Mo
Xiang Tao, Naiqing Zhao, Hongyan Jin, Zhenbo Zhang, Yintao Liu, Jian Wu, Robert C Bast Jr, Yinhua Yu and Youji Feng
Recent studies have suggested that FSH plays an important role in ovarian epithelial carcinogenesis. We demonstrated that FSH stimulates the proliferation and invasion of ovarian cancer cells, inhibits apoptosis and facilitates neovascularisation. Our previous work has shown that transient receptor potential channel C3 (TRPC3) contributes to the progression of human ovarian cancer. In this study, we further investigated the interaction between FSH and TRPC3. We found that FSH stimulation enhanced the expression of TRPC3 at both the mRNA and protein levels. siRNA-mediated silencing of TRPC3 expression inhibited the ability of FSH to stimulate proliferation and blocked apoptosis in ovarian cancer cell lines. FSH stimulation was associated with the up-regulation of TRPC3, while also facilitating the influx of Ca2 + after treatment with a TRPC-specific agonist. Knockdown of TRPC3 abrogated FSH-stimulated Akt/PKB phosphorylation, leading to decreased expression of downstream effectors including survivin, HIF1-α and VEGF. Ovarian cancer specimens were analysed for TRPC3 expression; higher TRPC3 expression levels correlated with early relapse and worse prognosis. Association with poor disease-free survival and overall survival remained after adjusting for clinical stage and grade. In conclusion, TRPC3 plays a significant role in the stimulating activity of FSH and could be a potential therapeutic target for the treatment of ovarian cancer, particularly in postmenopausal women with elevated FSH levels.
Yu-Feng Tian, Chi-Hong Chu, Mei-Hsuan Wu, Chia-Lin Chang, Tsan Yang, Yu-Ching Chou, Giu-Cheng Hsu, Cheng-Ping Yu, Jyh-Cherng Yu and Chien-An Sun
Adiponectin is a peptide hormone secreted exclusively by adipocytes, and obesity is an established risk factor for breast cancer. We have, thus, evaluated the associations of anthropometric measures of adiposity and adiponectin with the development of breast cancer in a case–control study. Questionnaire information, anthropometric measures, and blood samples were taken before treatment from 244 incident cases with breast cancer, including 141 premenopausal and 103 postmenopausal cases, and 244 controls admitted for health examination at the Tri-Service General Hospital, Taipei between 2004 and 2005. Plasma levels of adiponectin were measured by RIA. The relationship between anthropometric measures of adiposity and breast cancer risk was modified by menopausal status, with a significant increase in risk observed in postmenopausal but not premenopausal women. Moreover, a fairly robust inverse association of adiponectin with the risk was observed only in postmenopausal women (adjusted odds ratio (OR), 0.55; 95% confidence interval (CI), 0.23–0.97), but not in premenopausal women. Additionally, the plasma adiponectin levels tended to be inversely associated with estrogen receptor (ER)-positive (adjusted OR, 0.53; 95% CI, 0.27–0.98) but not ER-negative breast tumors. Furthermore, the associations of adiponectin with breast cancer risk overall and by menopausal and ER status remained after adjustment for obesity indices. These results suggest that adiponectin may have an independent role in breast carcinogenesis, particularly in the postmenopausal and ER-positive breast cancer risk.