Endocrine-related cancer最新文献

Men with high-risk, non-metastatic prostate cancer receive adjuvant androgen deprivation therapy (ADT) for at least 2 years according to Danish guidelines. It remains unclarified if patients regain the function of the pituitary-testis axis after cessation of ADT. Thus, we aimed to investigate the function of the pituitary-testis axis following adjuvant ADT. In this study, we included men who underwent external beam radiation therapy and ADT for high-risk prostate cancer. All patients underwent assessment of testosterone deficiency (TD) symptoms, full biochemical assessment of the pituitary-testis axis, and dynamic stimulatory tests of gonadotropin (gonadotropin-releasing hormone (GnRH) test) and testosterone production (human chorionic gonadotrophin (hCG) test). Patients were diagnosed with TD based on a combination of TD symptoms and testosterone below age-specific reference ranges. TD was characterized as primary, secondary, or mixed based on serum gonadotropins and stimulatory tests. We found that among the 51 patients included in the study, the median time on ADT was 3.2 years and median time since ADT cessation was 3.8 years. Twenty-eight patients were diagnosed with TD; 10 had primary TD (testicular dysfunction), 11 secondary TD (pituitary dysfunction), and 7 mixed TD (combined pituitary and testicular dysfunction). An inadequate testosterone response to hCG stimulation was shown in 42 patients, whereas only 11 patients had a subnormal gonadotropin response to GnRH. We conclude that persistent TD is a common long-term consequence of adjuvant ADT in prostate cancer survivors, equally distributed between pituitary and testicular dysfunction. The study emphasizes the necessity for systematic follow-up of full pituitary-testis axis function in patients receiving adjuvant ADT.

Papillary thyroid cancer (PTC) is one of the histological subtypes of thyroid cancer which is the most common endocrine malignancy in the world. The disrupted balance of the adenosine-to-inosine (A-to-I) RNA editing due to dysregulation of the editing genes exists in thyroid cancer. However, it is still largely unknown how functional single-nucleotide polymorphisms (SNPs) in the A-to-I RNA editing genes contribute to PTC genetic susceptibility. In this study, we systematically annotated and investigated the role of 28 potential functional SNPs of ADAR, ADARB1, ADARB2 and AIMP2 in PTC. We identified ADARB2 rs904957 and rs1007147 genetic variants which are associated with significantly elevated PTC risk in two case-control sets consisting of 2020 PTC cases and 2021 controls. Further investigations disclosed that ADARB2 could inhibit cell viability and invasion capabilities of PTC cells as a novel tumor suppressor. The ADARB2 rs904957 thymine-to-cytosine (T-to-C) polymorphism in gene 3'-untranslated region enhances miR-1180-3p-binding affinity and represses ADARB2 expression through an allele-specific manner. In line with this, carriers with the rs904957 C allele correlated with decreased tumor suppressor ADARB2 expression in tissue specimens showed notably increased risk of developing PTC compared to the T allele carriers. Our findings highlight that the A-to-I RNA editing gene ADARB2 SNPs confer PTC risk. Importantly, these insights would improve our understanding for the general roles of RNA editing and editing genes during cancer development.

TAGLN2, an actin-binding protein, functions as a binding protein to actin to facilitate the formation of intracellular cytoskeleton structures. TAGLN2 overexpression in papillary thyroid carcinoma (PTC) is reported in our previous study. This study aimed to examine the functions and molecular mechanisms of TAGLN2 in PTC. The clinical data analysis showed that TAGLN2 expression was associated with cervical lymph node metastasis in PTC. Gain- and loss-of-function approaches, as well as various cellular function, gene expression profiles, quantitative proteomics, and molecular biology experiments, were further exploited to explore the roles of TAGLN2 in PTC. The results showed that TAGLN2 overexpression significantly promoted the invasion of PTC cell lines (K1, TPC-1, and BCPAP). Besides, the results also indicated that TAGLN2 was associated with regulating proliferation, migration, angiogenesis, and adhesion of PTC cells. Gene expression profile, quantitative proteomics, and Western blotting were performed to identify the relevant pathways and key downstream molecules, and Rap1/PI3K/AKT signalling pathway, ITGB5, LAMC2, CRKL, vimentin, N-cadherin, and E-cadherin were finally focused on. Moreover, rescue experiments validated the involvement of the Rap1/PI3K/AKT signalling pathway in the TAGLN2-mediated invasion of PTC cells. Therefore, TAGLN2 may promote the invasion of PTC cells via the Rap1/PI3K/AKT signalling pathway and may be served as a potential therapeutic target for PTC. Developing antagonists targeting TAGLN2 may be a potentially effective therapeutic strategy for PTC.

Tumor uptake of exogenous cholesterol has been associated with the proliferation of various cancers. Previously, we and others have shown that hypercholesterolemia promotes tumor growth and silencing of the LDL receptor (LDLR) in high LDLR-expressing tumors reduces growth. To advance understanding of how LDL uptake promotes tumor growth, LDLR expression was amplified in breast cancer cell lines with endogenously low LDLR expression. Murine (Mvt1) and human (MDA-MB-468) breast cancer cell lines were transduced to overexpress human LDLR (LDLROE). Successful transduction was confirmed by RNA and protein analysis. Fluorescence-labeled LDL uptake was increased in both Mvt1 and MDA-MD-468 LDLROE cells. The expression of the cholesterol-metabolizing genes, ABCA1 and ABCG1, was increased, while HMGCR was decreased in the MDA-MB-468 LDLROE cells. In contrast, Mvt1 LDLROE cells showed no differences in Abca1 and Abcg1 expression and increased Hmgcr expression. Using a Seahorse analyzer, Mvt1 LDLROE cells showed increased respiration (ATP-linked and maximal) relative to controls, while no statistically significant changes in respiration in MDA-MB-468 LDLROE cells were observed. Growth of LDLROE cells was reduced in culture and in hypercholesterolemic mice by two-fold. However, the expression of proliferation-associated markers (Ki67, PCNA and BrdU-label incorporation) was not decreased in the Mvt1 LDLROE tumors and cells. Caspase-3 cleavage, which is associated with apoptosis, was increased in both the Mvt1 and MDA-MB-468 LDLROE cells relative to controls, with the Mvt1 LDLROE cells also showing decreased phosphorylation of p44/42MAPK. Taken together, our work suggests that while additional LDL can promote tumor growth, unregulated and prolonged LDL uptake is detrimental.

In a previous systematic review and meta-analysis of studies reporting associations between hyper-/hypothyroidism and breast cancer incidence published through 29 January 2019, we identified a higher risk with diagnosed hyperthyroidism compared to euthyroidism, but no association with diagnosed hypothyroidism. This 2-year updated meta-analysis aims to investigate the role of menopause in this association and the dose-response relationship with blood levels of thyroid-stimulating hormone (TSH) and thyroid hormones. After the exclusion of studies with only mortality follow-up, with thyroid dysfunction evaluated as a cancer biomarker or after prior breast cancer diagnosis, we reviewed 25 studies that were published up to 01 December 2021 and identified in MEDLINE, the COCHRANE library, Embase, or Web of Science; of these, 9 were included in the previous meta-analysis. Risk estimates from 22 of the 25 studies were included in the meta-analysis and pooled using random-effects models. Compared to euthyroidism, hyperthyroidism and hypothyroidism diagnoses were associated with higher (pooled risk ratio (RR): 1.12, 95% CI: 1.06-1.18, 3829 exposed cases) and lower risks (RR = 0.93, 95% CI: 0.86-1.00, 5632 exposed cases) of breast cancer, respectively. The increased risk after hyperthyroidism was greater among postmenopausal women (RR = 1.19, 95% CI 1.09-1.30) and the decreased risk after hypothyroidism was more pronounced among premenopausal women (RR = 0.69, 95% CI 0.53-0.89). Among women with no prior history of thyroid disease, every 1 mIU/L increase in TSH level was associated with a 0.8% (95% CI > 0-1.5%) lower risk of breast cancer. In conclusion, this meta-analysis supports an association between thyroid hormone levels and breast cancer risk, which could be modified by menopausal status.

Multiple endocrine neoplasia 4 (MEN4) is a rare multiglandular endocrine neoplasia syndrome clinically hallmarked by primary hyperparathyroidism (PHPT), pituitary adenoma (PitAd), and neuroendocrine tumors (NET), clinically overlapping MEN1. The underlying mutated gene - CDKN1B, encodes for the cell-cycle regulator p27. Possible genotype-phenotype correlations in MEN4 have not been thoroughly assessed. Prompted by the findings in three Israeli MEN4 kindreds, we performed a literature review on published and unpublished data from previously reported MEN4/CDKN1B cases. Univariate analysis analyzed time-dependent risks for developing PHPT, PitAd, or NET by variant type and position along the gene. Overall, 74 MEN4 cases were analyzed. PHPT risk was 53.4% by age 60 years (mean age at diagnosis age 50.6 ± 13.9 years), risk for PitAd was 23.2% and risk for NET was 16.2% (34.4 ± 21.4 and 52.9 ± 13.9 years, respectively). The frameshift variant p.Q107fs was the most common variant identified (4/41 (9.7%) kindreds). Patients with indels had higher risk for PHPT vs point mutations (log-rank, P = 0.029). Variants in codons 94-96 were associated with higher risk for PHPT (P < 0.001) and PitAd (P = 0.031). To conclude, MEN4 is clinically distinct from MEN1, with lower risk and older age for PHPT diagnosis. We report recurrent CDKN1B frameshift variants and possible genotype-phenotype correlations.

It has long been recognised that cancer cells critically depend on reprogrammed patterns of metabolism that can enable robust and abnormally high levels of cell proliferation. As mitochondria form hubs of cellular metabolic activity, it is reasonable to propose that pathways within these organelles can form targets that can be manipulated to compromise the ability of cancer cells to cause disease. However, mitochondria are highly multi-functional, and the full range of mechanistic inter-connections are still being unravelled to enable the full potential of targeting mitochondria in cancer therapeutics. Here, we aim to highlight the potential of modulating mitochondrial dynamics to target key metabolic or apoptotic pathways in cancer cells. Distinct roles have been demonstrated for mitochondrial fission and fusion in different cancer contexts. Targeting of factors mediating mitochondrial dynamics may be directly related to impairment of oxidative phosphorylation, which is essential to sustain cancer cell growth and can also alter sensitivity to chemotherapeutic compounds. This area is still lacking a unified model, although further investigation will more comprehensively map the underlying molecular mechanisms to enable better rational therapeutic strategies based on these pathways.

Mitochondrial DNA (mtDNA) alterations have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is little information about its involvement in pheochromocytomas and paragangliomas (PCCs/PGLs) formation. PCCs and PGLs are rare endocrine tumors of the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia that can synthesize and secrete catecholamines. Over the last 3 decades, the genetic background of about 60% of PCCs/PGLs involving nuclear DNA alterations has been determined. Recently, a study showed that mitochondrial alterations can be found in around 17% of the remaining PCCs/PGLs. In this review, we summarize recent knowledge regarding both nuclear and mitochondrial alterations and their involvement in PCCs/PGLs. We also provide brief insights into the genetics and the molecular pathways associated with PCCs/PGLs and potential therapeutical targets.

The pharmacological approach to adrenocortical carcinoma (ACC) is based on mitotane with/without etoposide, doxorubicin, and cisplatin, according to the disease stage. Considering the limited efficacy and toxicity of this treatment, new strategies are required. Trabectedin is a marine-derivated antitumoral agent that inhibits oncogenic transcription. We have already demonstrated trabectedin cytotoxic activity at sub-nanomolar concentrations in ACC cells. Here, we expanded the investigation of trabectedin effect on ACC preclinical models, evaluating whether trabectedin could affect ACC cells' invasiveness and metastasis formation. NCI-H295R, MUC-1, and TVBF-7 cell lines were used. Cell tumor xenografts in Danio rerio embryos were performed. The tumor mass areas and the number of embryos with metastasis were evaluated. The in vitro invasiveness of cells was evaluated. Effects of trabectedin of MMP2, TIMP1, and TIMP2 were evaluated at gene level qRT-PCR. MMP2 secreted in the cell medium was evaluated by Western blot and by zymography. Xenograft experiments demonstrated that trabectedin significantly reduced the tumor area in each ACC cell model and metastasis formation in embryos injected with metastasis-derived cell lines. Trabectedin treatment reduced the invasiveness of ACC cells across the matrix, which was greater at baseline for the metastatic models. In metastatic cell models, protein analysis demonstrated a reduction of MMP2 secretion and activity in the culture medium after treatment. Our results indicate that trabectedin interferes with invasiveness and metastasis processes, both dramatic features of ACC. Furthermore, these results support those previously published in providing the rationale for a clinical evaluation of the efficacy of trabectedin in ACC patients.

Prostate cancer research suffers from the lack of suitable models to study the role of normal cells in prostate carcinogenesis. To address this challenge, we developed a cell line model mimicking luminal prostate epithelial cells by modifying the immortalized prostate epithelial cell line RWPE-1 to constitutively express the androgen receptor (AR). RWPE-1-AR cells express known AR target genes, and exhibit coexpression of luminal and basal markers characteristic of transient amplifying cells, and an RNA signature resembling prostate luminal progenitor cells. Under unstimulated conditions, constitutive AR expression does not have a biologically significant effect on the proliferation of RWPE-1 cells, but when stimulated by androgens, growth is retarded. The transcriptional response of RWPE-1-AR cells to androgen stimulation involves suppression of the growth-related KRAS pathway and is thus markedly different from that of the prostate cancer cell line LNCaP and its derivative AR-overexpressing LNCaP-ARhi cells, in which growth- and cancer-related pathways are upregulated. Hence, the nonmalignant AR-positive RWPE-1-AR cell line model could be used to study the transformation of the prostate epithelium.