0
selected
-
1.
Orphan nuclear receptors as regulators of intratumoral androgen biosynthesis in castration-resistant prostate cancer.
Zhou, J, Wang, Y, Wu, D, Wang, S, Chen, Z, Xiang, S, Chan, FL
Oncogene. 2021;(15):2625-2634
-
-
Free full text
-
Abstract
Castration-resistant prostate cancer (CRPC) almost invariably occurs after androgen-deprivation therapy (ADT) for the advanced metastatic disease. It is generally believed that among multiple mechanisms and signaling pathways, CRPC is significantly driven by the reactivation of androgen receptor (AR) signaling in ADT-treated patients with castrate levels of androgen, partially at least mediated by the androgen biosynthesis within the tumor, also known as intratumoral or intraprostatic androgen biosynthesis. Steroidogenic enzymes, such as CYP11A1, CYP17A1, HSD3B1, AKR1C3 and SRD5A, are essential to catalyze the conversion of the initial substrate cholesterol into potent androgens that confers the CRPC progression. Accumulating evidences indicate that many steroidogenic enzymes are upregulated in the progression setting; however, little is known about the dysregulation of these enzymes in CRPC. Orphan nuclear receptors (ONRs) are members of the nuclear receptor superfamily, of which endogenous physiological ligands are unknown and which are constitutively active independent of any physiological ligands. Studies have validated that besides AR, ONRs could be the potential therapeutic targets for prostate cancer, particularly the lethal CRPC progression. Early studies reveal that ONRs play crucial roles in the transcriptional regulation of steroidogenic enzyme genes. Notably, we and others show that three distinct ONRs, including liver receptor homolog-1 (LRH-1, NR5A2), steroidogenic factor 1 (SF-1, AD4BP, NR5A1) and estrogen-related receptor α (ERRα, NR3B1), can contribute to the CRPC progression by promotion of the intratumoral androgen synthesis via their direct transcriptional regulation on multiple steroidogenic enzymes. This review presents an overview of the current understanding on the intratumoral androgen biosynthesis in CRPC, with a special focus on the emerging roles of ONRs in this process.
-
2.
Blood biomarkers of bone metastasis in digestive tract malignant tumors.
Ma, X, Fan, Y, Chen, Z, Zhang, Y, Wang, S, Yu, J
Future oncology (London, England). 2021;(12):1507-1518
Abstract
Aim: To evaluate the role of clinical features and blood markers in patients with malignant digestive tract tumors bone metastasis. Materials & methods: A total of 267 patients were included in this trial. Age, gender, primary tumor site, metastatic sites, T/N stage, high-density lipoprotein, low-density lipoprotein, total cholesterol, triglycerides, alkaline phosphatase, LDH, Ca levels, platelet, neutrophils to absolute value of lymphocytes (NLR), ratio of platelets to absolute values of lymphocytes (PLR) were analyzed. Results: T stage, lymph node metastasis, N stage and liver and lung metastasis were independent risk factors. LDH + alkaline phosphatase + NLR + PLR and LDH + NLR, respectively have higher predictive value for bone metastasis compared with patients with early-stage malignant digestive tract tumor and patients with advanced malignant digestive tract tumor without bone metastasis. Conclusion: Some clinical features or blood markers have the potential to detect bone metastasis early to avoid skeletal complications.
-
3.
Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.
Guo, X, Lin, W, Wen, W, Huyghe, J, Bien, S, Cai, Q, Harrison, T, Chen, Z, Qu, C, Bao, J, et al
Gastroenterology. 2021;(4):1164-1178.e6
-
-
Free full text
-
Abstract
BACKGROUND AND AIMS Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. METHODS Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. RESULTS We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. CONCLUSIONS Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
-
4.
Characteristics and prognosis analysis of additional chromosome abnormalities in newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide as the front-line therapy.
Lou, Y, Suo, S, Tong, H, Ye, X, Wang, Y, Chen, Z, Qian, W, Meng, H, Mai, W, Huang, J, et al
Leukemia research. 2013;(11):1451-6
Abstract
Currently, there are few studies that address the prognostic significance of baseline additional chromosomal abnormalities (ACAs) in newly diagnosed acute promyelocytic leukemia (APL) patients treated with arsenic trioxide (ATO) as the front-line therapy. A series of 271 consecutive APL patients has been cytogenetically investigated between 2004 and 2011 in our institution. The incidence of ACAs was 27% (46/172) in APL cases with t(15;17). Trisomy 8 was the most recurrent abnormality, accounting for 30% (14/46) of patients with ACAs, followed by +21 (7%, 3/46) and -7/7q (7%, 3/46). Nine cases (14.1%) were found to have additional balanced translocation aberrations, most of them are new and non-recurrent. Treatment protocols consisted of all-trans retinoic acid (ATRA) and chemotherapy with or without the ATO therapy. Overall, patients with and without ACAs had similar complete remission (CR) rates (94% and 98%, respectively, P=0.344). With a median follow-up of 41 months, univariate analysis showed that ACAs did not show any prognostic significance in relapse-free survival (RFS) and overall survival (OS). In addition, ATO treatment was an independent favorable predictor for RFS. Thus, this data provides insights into cytogenetic features of APL, and suggests that ATO-based combination therapy improved RFS in de novo APL patients, while ACAs had no impact on prognosis.