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Inga-Lena Nilsson, Jan Zedenius, Li Yin and Anders Ekbom

In order to evaluate the link between primary hyperparathyroidism (pHPT) and malignancies, cases subjected to parathyroid adenomectomy (PTX) during 1958–1997 in Sweden were identified by analyzing the National Swedish Cancer Registry. To minimize the influence of confounding by detection, cases with malignant disease diagnosed before or at the same time as pHPT or during the first year after PTX were excluded. Altogether 9782 cases (7642♀) were included and followed for up to 40 years. Thus, the study comprises 89 571 person-years of observation. The incidence of malignancies was compared with that in the Swedish population standardized for age, sex, and calendar year. An increased overall incidence of cancer was demonstrated in both genders (standardized incidence ratio (SIR) 1.43, 95% confidence interval (CI) 1.35–1.52). This remain unchanged beyond 15 years after PTX. Breast cancer contributed a quarter of the cancer incidence in women (SIR 1.44, 95% CI 1.25–1.62). An increased risk of kidney (SIR 2.40, 95% CI 1.72–3.25), colonic (SIR 1.46, 95% CI 1.19–1.77), and squamous cell skin cancer (SIR 2.79, 95% CI 2.25–3.43) was found in both genders. The risk of endocrine and pancreas cancer was increased in the minority of patients who had their PTX before the age of 40. We conclude that pHPT is associated with an increased risk of developing malignancies that persists even after PTX. This suggests a causal disassociation with the biochemical derangements caused by parathyroid adenoma, while potentially common etiological mechanisms may include genetic predisposition or acquired disability to withstand environmental influence.

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De-tao Yin, Wenxun Wu, Mingchuang Li, Qi-en Wang, Hongqiang Li, Yongfei Wang, Yifeng Tang and Mingzhao Xing

The expression of the Dickkopf homolog 3 (DKK3) gene is downregulated in some human cancers, suggesting a possible tumor suppressor role of this gene. The role and regulation of DKK3 in thyroid cancer have not been examined. In this study, we explored the relationship of promoter methylation with the inactivation of DKK3 and tumor behaviors in papillary thyroid carcinoma (PTC). We used methylation-specific PCR and RT-PCR to examine the promoter methylation and expression of DKK3 and tumor characteristics. We found mRNA expression of DKK3 in 44.9% of the PTC tissue samples vs 100% of the matched normal thyroid tissue samples (P<0.01). In contrast, an opposite distribution pattern of DKK3 gene methylation was observed; specifically, 38.8% of the PTC tissue samples vs 0% of the matched normal thyroid tissue samples harbored DKK3 methylation. An inverse correlation between the promoter methylation and mRNA expression of DKK3 in PTC tissue samples was also observed. Moreover, we also found an inverse correlation between DKK3 expression and some aggressive pathological characteristics of PTC, including high TNM stages and lymph node metastasis, but a positive correlation between DKK3 promoter hypermethylation and pathological aggressiveness of the tumor. Treatment of the PTC cell line TPC-1 with the demethylating agent 5-azaC reduced DKK3 promoter methylation and enhanced its expression, establishing functionally the impact of DKK3 methylation on its expression. Our data thus for the first time demonstrate that the DKK3 gene is a potential tumor suppressor gene in thyroid cancer and that aberrant promoter methylation is an important mechanism for its downregulation, which may play a role in the tumorigenesis and aggressiveness of PTC.

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Xiao-hui Luo, Jian-zhou Liu, Bo Wang, Qun-li Men, Yu-quan Ju, Feng-yan Yin, Chao Zheng and Wei Li

Insights into the mechanisms by which key factors stimulate cell growth under androgen-depleted conditions is a premise to the development of effective treatments with clinically significant activity in patients with castration-resistant prostate cancer (CRPC). Herein, we report that, the expression of Krüppel-like factor 14 (KLF14), a master transcription factor in the regulation of lipid metabolism, was significantly induced in castration-insensitive PCa cells and tumor tissues from a mouse xenograft model of CRPC. KLF14 upregulation in PCa cells, which was stimulated upstream by oxidative stress, was dependent on multiple pathways including PI3K/AKT, p42/p44 MAPK, AMPK and PKC pathways. By means of ectopic overexpression and genetic inactivation, we further show that KLF14 promoted cell growth via positive regulation of the antioxidant response under androgen-depleted conditions. Mechanistically, KLF14 coupled to p300 and CBP to enhance the transcriptional activation of HMOX1, the gene encoding the antioxidative enzyme heme oxygenase-1 (HO-1) that is one of the most important mechanisms of cell adaptation to stress. Transient knockdown of HMOX1 is sufficient to overcome KLF14 overexpression-potentiated PCa cell growth under androgen-depleted conditions. From a pharmacological standpoint, in vivo administration of ZnPPIX (a specific inhibitor of HO-1) effectively attenuates castration-resistant progression in the mouse xenograft model, without changing KLF14 level. Together, these results provide comprehensive insight into the KLF14-dependent regulation of antioxidant response and subsequent pathogenesis of castration resistance and indicate that interventions targeting the KLF14/HO-1 adaptive mechanism should be further explored for CRPC treatment.

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Yi-Lin Chang, Yu-Kan Hsu, Tsung-Fan Wu, Chieh-Ming Huang, Li-Yin Liou, Ya-Wen Chiu, Yu-Hsuan Hsiao, Fuh-Jinn Luo and Ta-Chun Yuan

Estrogen receptor α (ERA) is a DNA-binding transcription factor that plays an important role in the regulation of cell growth. Previous studies indicated that the expression of ERα in cell lines and tumors derived from oral squamous cell carcinoma (OSCC). The aim of this study was to examine the activity and function of ERα in OSCC cells and the mechanism underlying ERα activation. Immunochemical analyses in benign (n=11) and malignant (n=21) lesions of the oral cavity showed that ERα immunoreactivity was observed in 43% (9/21) of malignant lesions, whereas none of benign lesions showed ERα immunoreactivity. The ERα expression was also found in three OSCC cell lines and its transcriptional activity was correlated with cell growth. Addition of estradiol stimulated cell growth, whereas treatment of tamoxifen or knockdown of ERα expression caused reduced cell growth. Interestingly, the expression and activity of focal adhesion kinase (FAK) were associated with the phosphorylation of ERα at serine 118 in OSCC cells. Elevated expression of FAK in the slow-growing SCC25 cells caused increases in ERα phosphorylation, transcriptional activity, and cell growth rate, whereas knockdown of FAK expression in the rapid-growing OECM-1 cells led to reduced ERα phosphorylation and activity and retarded cell growth. Inhibition of the activity of protein kinase B (AKT), but not ERK, abolished FAK-promoted ERα phosphorylation. These results suggest that OSCC cells expressed functional ERα, whose activity can be enhanced by FAK/AKT signaling, and this was critical for promoting cell growth. Thus, FAK and ERα can serve as the therapeutic targets for the treatment of OSCC.

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Hongbing Chen, Yin Sun, Chengyu Wu, Clara E Magyar, Xinmin Li, Liang Cheng, Jorge L Yao, Steven Shen, Adeboye O Osunkoya, Chaozhao Liang and Jiaoti Huang

Small cell neuroendocrine carcinoma (SCNC) of the prostate is a variant form of prostate cancer that occurs de novo or as a recurrent tumor in patients who received hormonal therapy for prostatic adenocarcinoma. It is composed of pure neuroendocrine (NE) tumor cells, but unlike the scattered NE cells in benign prostate and adenocarcinoma that are quiescent, the NE cells in SCNC are highly proliferative and aggressive, causing death in months. In this study, we provide evidence that interleukin 8 (IL8)–CXCR2–P53 (TP53) signaling pathway keeps the NE cells of benign prostate and adenocarcinoma in a quiescent state normally. While P53 appears to be wild-type in the NE cells of benign prostate and adenocarcinoma, immunohistochemical studies show that the majority of the NE tumor cells in SCNC are positive for nuclear p53, suggesting that the p53 is mutated. This observation is confirmed by sequencing of genomic DNA showing p53 mutation in five of seven cases of SCNC. Our results support the hypothesis that p53 mutation leads to inactivation of the IL8–CXCR2–p53 signaling pathway, resulting in the loss of an important growth inhibitory mechanism and the hyper-proliferation of NE cells in SCNC. Therefore, we have identified potential cells of origin and a molecular target for prostatic SCNC that are very different from those of conventional adenocarcinoma, which explains SCNC's distinct biology and the clinical observation that it does not respond to hormonal therapy targeting androgen receptor signaling, which produces short-term therapeutic effects in nearly all patients with prostatic adenocarcinoma.

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Fei Han, Wen-bin Liu, Jian-jun Li, Ming-qian Zhang, Jun-tang Yang, Xi Zhang, Xiang-lin Hao, Li Yin, Cheng-yi Mao, Xiao Jiang, Jia Cao and Jin-yi Liu

New potential biomarkers and therapeutic targets for ovarian cancer should be identified. The amplification in chromosomal region 5q31-5q35.3 exhibits the strongest correlation with overall survival (OS) of ovarian cancer. SOX30 coincidentally located at this chromosomal region has been determined as a new important tumor-suppressor. However, the prognostic value, role and mechanism of SOX30 in ovarian cancer are unexplored. Here, we revea1 that SOX30 is frequently over-expressed in ovarian cancer tissues, and is associated with clinical-stage and metastasis of ovarian cancer patients. High SOX30 expression predicts better OS and acts as an independent prognostic factor in advanced-stage patients, but is not associated with OS in early-stage patients. Based on the survival analyses, the advanced-stage patients with high SOX30 expression can receive the platin and/or taxol based chemotherapy, whereas should not receive chemotherapy containing gemcitabine or topotecan. Functionally, SOX30 strongly inhibits tumor cell migration and invasion in intro, and suppresses tumor metastasis in vivo. SOX30 regulates markers (E-cadherin, Fibronectin, N-cadherin and Vimentin) and prevents the characteristics of epithelial-mesenchymal transition (EMT). SOX30 transcriptionally regulates the expression of E-cadherin, Fibronectin and N-cadherin by binding to their promoters. Restoration of E-cadherin and/or N-cadherin when over-expressing SOX30 significantly reduces the anti-metastatic role of SOX30. Indeed, chemotherapy treatment containing platin or gemcitabine combined with SOX30 expression influences tumor cell metastasis and the survival of nude mice differently, which is closely associated with EMT. In conclusion, SOX30 antagonizes tumor metastasis via preventing EMT process that can be used to predict survival and incorporated into chemotherapeutics of advanced-stage ovarian cancer patients.