Xiongfei Yu

Estrogen receptor-α36 is involved in development of acquired tamoxifen resistance via regulating the growth status switch in breast cancer cells

Acquired tamoxifen (TAM) resistance limits the therapeutic benefit of TAM in patients with hormone‐dependent breast cancer. The switch from estrogen‐dependent to growth factor‐dependent growth is a critical step in this process. However, the molecular mechanisms underlying this switch remain poorly understood. In this study, we established a TAM resistant cell sub line (MCF‐7/TAM) from estrogen receptor‐α (ER‐α66) positive breast cancer MCF‐7 cells by culturing ER‐α66‐positive MCF‐7 cells in medium plus 1 μM TAM over 6 months. MCF‐7/TAM cells were then found to exhibit accelerated proliferation rate together with enhanced in vitro migratory and invasive ability. And the estrogen receptor‐α36 (ER‐α36), a novel 36‐kDa variant of ER‐α66, was dramatically overexpressed in this in vitro model, compared to the parental MCF‐7 cells. Meanwhile, the expression of epidermal growth factor receptor (EGFR) in MCF‐7/TAM cells was significantly up‐regulated both in mRNA level and protein level, and the expression of ER‐α66 was greatly down‐regulated oppositely. In the subsequent studies, we overexpressed ER‐α36 in MCF‐7 cells by stable transfection and found that ER‐α36 transfected MCF‐7 cells (MCF‐7/ER‐α36) similarly exhibited decreased sensitivity to TAM, accelerated proliferative rate and enhanced in vitro migratory and invasive ability, compared to empty vector transfected MCF‐7 cells (MCF‐7/V). Real‐time qPCR and Western blotting analysis revealed that MCF‐7/ER‐α36 cells possessed increased EGFR expression but decreased ER‐α66 expression both in mRNA level and protein level, compared to MCF‐7/V cells. This change in MCF‐7/ER‐α36 cells could be reversed by neutralizing anti‐ER‐α36 antibody treatment. Furthermore, knock‐down of ER‐α36 expression in MCF‐7/TAM cells resulted in reduced proliferation rate together with decreased in vitro migratory and invasive ability. Decreased EGFR mRNA and protein expression as well as increased ER‐α66 mRNA expression were also observed in MCF‐7/TAM cells with down‐regulated ER‐α36 expression. In addition, blocking EGFR/ERK signaling in MCF‐7/ER‐α36 cells could restore the expression of ER‐α66 partly, suggesting a regulatory function of EGFR/ERK signaling in down‐regulation of ER‐α66 expression. In conclusion, our results indicated for the first time a regulatory role of ER‐α36 in up‐regulation of EGFR expression and down‐regulation of ER‐α66 expression, which could be an underlying mechanism for the growth status switch in breast tumors that contribute to the generation of acquired TAM resistance. And ER‐α36 could be considered a potential new therapeutic target in breast tumors which have acquired resistance to TAM.

Estrogen-independent effects of ER-α36 in ER-negative breast cancer.

Estrogen receptor-alpha 36 (ER-α36) is a variant of ER-α that has been found to be expressed in conventional ER (ER-α66)-negative breast cancer cell lines and human breast cancer samples. In this study, we found that, using immunohistochemical study, ER-α36 expression was significantly higher in ER-negative tumors than in ER-positive tumors although the expression was not associated with other clinicopathological characteristics. We then constructed an ER-α36-specific microRNA hairpin vector and established stable ER-α36 knockdown cells, and found that the knockdown cells were more sensitive to paclitaxel; the c-Jun N-terminal kinase pathway appeared to be involved in the mechanism. Downregulation of ER-α36 also resulted in decreased migration and invasion. These changes were estrogen independent. Our findings indicated that target ER-α36 may be a strategy for treating ER-negative breast cancers.

LncRNAs: emerging biomarkers in gastric cancer

Long noncoding RNAs (lncRNAs) recently have been recognized as having a critical role in cancer development and progression. Gastric cancer remains a major clinical challenge worldwide owing to poor prognosis and limited treatment options. Accumulating studies have demonstrated that lncRNAs may play an active role in tumorigenesis, metastasis, prognosis and drug resistance of gastric cancer. Here, we collect recent knowledge to show differential expression of lncRNA in gastric cancer and their underlying mechanism of activities in gastric cancer involved in epigenetic, transcription and post-transcriptional processing. This review focuses on the regulation and function of gastric cancer-related lncRNAs and provides an overview of current effects to exploit them to be potential biomarkers and therapeutic targets for gastric cancer.

Advances in the targeted therapy of liposarcoma.

Liposarcoma (LPS) is the most common type of soft-tissue sarcoma. Complete surgical resection is the only curative means for localized disease; however, both radiation and conventional cytotoxic chemotherapy remain controversial for metastatic or unresectable disease. An increasing number of trials with novel targeted therapy of LPS have provided encouraging data during recent years. This review will provide an overview of the advances in our understanding of LPS and summarize the results of recent trials with novel therapies targeting different genetic and molecular aberrations for different subtypes of LPS.

Indocyanine green clearance in evaluating the recovery of liver reserve function after superselective transarterial chemoembolization.

Transarterial chemoembolization (TACE) may ravage normal liver tissues apart from the neoplastic nodules which offset the anti-tumor effect. This study aimed to evaluate the recovery of liver reserve function (LRF) after TACE by indocyanine green (ICG) clearance test and other routine liver function tests. Forty-six newly diagnosed HCC patients who had undergone TACE as the initial treatment from January 2011 to January 2012 were enrolled in this study. The effects of age, basic ICG clearance rate and interval time between two assessments on the recovery of LRF were analyzed. We found that ICG retention rate at the 15 minutes (ICGR15) was significantly increased after TACE (12.3+/-8.1% vs 16.8+/-12.1%, P<0.01) in all the 46 patients. In particular, the ICGR15 value was increased in older patients (age>55 years, 20.3+/-12.5% vs 13.7+/-7.2%, P<0.01). The interval of ICG test also affected the ICGR15 value (≤47 days, 17.8+/-11.4% after vs 12.1+/-7.1% before TACE, P<0.01). Our data suggested that TACE decreased LRF, especially in older patients. ICG test was more sensitive to evaluate the recovery of LRF after TACE than the Child-Pugh grade and routine liver function tests.

The Prognostic Value of Intermedin in Patients with Breast Cancer

This study aimed to evaluate the prognostic value of preoperative plasma intermedin levels in breast cancer patients. Plasma intermedin levels of 252 breast cancer women and 100 healthy women were determined using radioimmunoassay kit. Adverse event was defined as first local recurrence, distant metastasis, second primary cancer of another organ, or death from any cause during 5-year follow-up. Disease-free survival was defined as the time between surgery and the date of any adverse event whichever appeared first. Overall survival was defined from surgery to death for any cause. The relationships between plasma intermedin levels and clinical outcomes of breast cancer patients were evaluated using multivariate analysis. The results showed that preoperative plasma intermedin levels were substantially higher in patients than in healthy subjects using t-test. Intermedin was identified as an independent predictor for 5-year mortality, adverse event, disease-free survival, and overall survival using multivariate analysis. Based on receiver operating characteristic curve analysis, preoperative plasma intermedin levels had high predictive value for 5-year mortality and adverse event. In conclusion, preoperative plasma intermedin levels are highly associated with poor patient outcomes and intermedin may be a potential prognostic biomarker for patients with breast cancer.

Clinicopathological and prognostic analysis of follicular thyroid carcinoma in a single institute over a 15-year period

BACKGROUND This study was to evaluate the clinicopathological and prognostic features of follicular thyroid carcinoma (FTC) in our institute over a 15-year period. METHODS The clinical features, management and outcome of 134 consecutive patients were analyzed according to the time of diagnosis: Group I (1997-2001), Group II (2002-2006), and Group III (2007-2011). RESULTS As time advanced, the ratio of FTC to papillary thyroid carcinoma decreased from 8.7% in group I to 4.3% in group III (p = 0.000). The percentage of patients undergoing total thyroidectomy seemed to be more commonly used in the later periods - from 10.5% in group I to 21.8% in group II and 18.9% in group III. The median diameter of tumors in group I was 4.2 cm and it showed a sharp decrease to 2.8 cm in group II and 2.9 cm in group III respectively. There was a trend towards a higher stage in patients from Group I vs. patients from Groups II and III (stage IV, 15.8% vs. 2.2% and 4.3%, p = 0.072). The outcome was improved in terms of disease-free survival (DFS). The 3-year DFS rate improved from 77.8% in group I to 93.7% in group II and 100% in group III (p = 0.008). CONCLUSIONS The clinical features, management and outcome of FTC patients changed over 15-year period. Patients diagnosed after 2001 had a better prognosis. This improvement was probably related to earlier diagnosis with smaller tumor size and presentation at earlier tumor stage.