Lipid accumulation exacerbates tumor development, as it fuels the proliferative growth of cancer cells. The role of medium-chain acyl-CoA dehydrogenase (ACADM), an enzyme that catalyzes the first step of mitochondrial fatty acid oxidation, in tumor biology remains elusive. Therefore, investigating its mode of dysregulation can shed light on metabolic dependencies in cancer development. In hepatocellular carcinoma (HCC), ACADM was significantly underexpressed, correlating with several aggressive clinicopathologic features observed in patients. Functionally, suppression of ACADM promoted HCC cell motility with elevated triglyceride, phospholipid, and cellular lipid droplet levels, indicating the tumor suppressive ability of ACADM in HCC. Sterol regulatory element-binding protein-1 (SREBP1) was identified as a negative transcriptional regulator of ACADM. Subsequently, high levels of caveolin-1 (CAV1) were observed to inhibit fatty acid oxidation, which revealed its role in regulating lipid metabolism. CAV1 expression negatively correlated with ACADM and its upregulation enhanced nuclear accumulation of SREBP1, resulting in suppressed ACADM activity and contributing to increased HCC cell aggressiveness. Administration of an SREBP1 inhibitor in combination with sorafenib elicited a synergistic antitumor effect and significantly reduced HCC tumor growth in vivo. These findings indicate that deregulation of fatty acid oxidation mediated by the CAV1/SREBP1/ACADM axis results in HCC progression, which implicates targeting fatty acid metabolism to improve HCC treatment. Significance: This study identifies tumor suppressive effects of ACADM in hepatocellular carcinoma and suggests promotion of β-oxidation to diminish fatty acid availability to cancer cells could be used as a therapeutic strategy.
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Rab GTPases are major mediators that ensure the proper spatiotemporal regulation of intracellular trafficking. Functional impairment and altered expression of Rab proteins have been revealed in various human cancers. There is an emerging evidence about the role of Rab proteins in the biogenesis of extracellular vesicles (EVs). In hepatocellular carcinoma (HCC), using RNA sequencing comparing expression profiles of adjacent non‐tumorous tissues and HCC, Rab20 is identified to be the most frequently downregulated Rab member in HCC. Functionally, restoration of Rab20 in metastatic HCC cells results in the release of EVs with a diminished activity to promote cell growth, motility and metastasis. Conversely, EVs released from normal liver cells with Rab20 knockdown loses suppressive effect on HCC cell growth and motility. Proteomic profiling revealed the level of triosephosphate isomerase 1 (TPI1), a glycolytic enzyme, in EVs to be positively associated with Rab20 expression of the releasing cells. TPI1 targeted to be expressed in EVs released by Rab20 knockdown cells compromises the oncogenic activity of EVs. Besides, EVs released by TPI1 knockdown cells recapitulates the promoting effect of EVs derived from HCC cells with Rab20 underexpression. Aerobic glycolysis is beneficial to the survival and proliferation of tumour cells. Here, we observed that the enhanced cell growth and motility are driven by the enhanced aerobic glycolysis induced by EVs with reduced TPI1. The addition of glycolytic inhibitor blocks the promoting effect of EVs with reduced TPI1. Taken together, our study provides a mechanistic link among tumour cell‐derived EVs and glucose metabolism in HCC with Rab20 deregulation.
BackgroundThe prognostic significance of size of central lymph node metastasis (CLNM) in papillary thyroid carcinoma (PTC) remains unknown. Because postsurgical detectable stimulated thyroglobulin (DsTg) after radioiodine ablation may imply persistent or recurrent disease, we evaluated the association between size of CLNM and rate of DsTg in patients with PTC who underwent unilateral prophylactic central neck dissection.MethodsTo be eligible for analysis, the prophylactic central neck dissection specimen with <3 central lymph nodes (CLNs) or size of CLNM ≥1 cm as measured under the microscope was excluded. Of 132 specimens, 89 (67.4 %) were eligible. Forty patients (44.9 %) had no metastasis or pN0, 20 (22.5 %) had micrometastasis (<2 mm) or pN1mic and 29 (32.6 %) had macrometastasis (≥2 mm) or pN1mac. Postablation sTg level was measured 9 months after surgery. A multivariable analysis was conducted to identify independent factors for postablation DsTg.ResultsLarger-sized CLNM correlated significantly with younger age (p = 0.028), greater number of CLN retrieved (p = 0.016), greater number of metastatic CLN excised (p < 0.001), higher metastatic CLN ratio (p = 0.006) and postablation sTg level (p = 0.012). In the multivariable analysis, after adjusting for tumor size and metastatic CLN ratio, size of CLNM was an independent predictor of postablation DsTg (odds ratio 1.56, 95 % confidence interval 1.09–2.24, p = 0.015). Relative to pN0, the odds ratios for postablation DsTg in pN1mic and pN1mac were 2.53 (95 % confidence interval 0.35–19.00, p = 0.351) and 5.81 (95 % confidence interval 1.22–27.70, p = 0.027), respectively.ConclusionsSize of CLNM was an independent factor for DsTg 9 months after surgery. Patients with pN1mac were almost 6 times more likely to have postablation DsTg than those with pN0 or pN1mic.
Androgen receptor (AR) is a master transcription factor that drives prostate cancer (PCa) development and progression. Alterations in the expression or activity of AR coregulators significantly impact the outcome of the disease. Using a proteomics approach, we identified the tripartite motif‐containing 33 (TRIM33) as a novel transcriptional coactivator of AR. We demonstrate that TRIM33 facilitates AR chromatin binding to directly regulate a transcription program that promotes PCa progression. TRIM33 further stabilizes AR by protecting it from Skp2‐mediated ubiquitination and proteasomal degradation. We also show that TRIM33 is essential for PCa tumor growth by avoiding cell‐cycle arrest and apoptosis, and TRIM33 knockdown sensitizes PCa cells to AR antagonists. In clinical analyses, we find TRIM33 upregulated in multiple PCa patient cohorts. Finally, we uncover an AR‐TRIM33‐coactivated gene signature highly expressed in PCa tumors and predict disease recurrence. Overall, our results reveal that TRIM33 is an oncogenic AR coactivator in PCa and a potential therapeutic target for PCa treatment.
Background Endocytosis is a fundamental process for internalizing small extracellular vesicles (sEVs). The present study aimed to elucidate the role of clathrin light chain A (CLTA) in sEV uptake in hepatocellular carcinoma (HCC). Materials and methods CLTA expression was analyzed by bioinformatics, quantitative PCR and immunohistochemistry. The clinical relevance of CLTA was analyzed by Fisher’s exact test, Kaplan–Meier analysis, and multivariate cox regression model. The functions of CLTA in sEV uptake and cancerous properties were examined by PKH67-sEV uptake, MTT, colony formation, and transwell assays. Mass spectrometry was used to identify the downstream effectors of CLTA. CLTA inhibitor, Pitstop 2, was tested in a mouse model of patient-derived xenografts (PDXs). Results CLTA expression was higher in tumor tissues than in non-tumorous liver tissues and progressively increased from the early to late tumor stage. CLTA overexpression was associated with larger tumor size and poor prognosis in HCC. Cellular CLTA contributed to the sEV uptake, resulting in enhanced cancerous properties. Mechanistically, CLTA increases capping actin protein gelsolin-like (CAPG) expression to facilitate sEV uptake, thereby promoting the proliferation, motility, and invasiveness of HCC cells. What’s more, the CLTA inhibitor Pitstop 2 alone or in combination with sorafenib attenuated tumor growth in mice implanted with PDXs. Conclusions The study reveals the role of CLTA in sEV uptake to promote HCC progression. Inhibition of CLTA and its mediated pathway illuminate a new therapeutic strategy for HCC patients.
Psychotropic medications are often used to treat problem behaviours in people with intellectual disability which not only occur frequently but also tend to persist over time. This study examined the pattern of prescription of such medications to manage problem behaviours for adults with intellectual disabilities in a specialist psychiatric unit in Hong Kong. Individuals aged 18 or above with problem behaviours and receiving psychotropic medication for treatment in hospital, outpatient and community settings were studied. Their demographic and clinical information was collected. The type and dosage of medications were retrieved from the computer database and analysed. Those with psychotic disorder and mood (affective disorder) were excluded. After screening, 236 patients met the inclusion criteria. People with moderate intellectual disability accounted for most of the cohort (46%). Autism spectrum disorder was the commonest psychiatric diagnosis (35%) and aggression the commonest problem behaviour (52%). Antipsychotics, mood stabilisers and antidepressants were prescribed to 96%, 20% and 13% of the subjects respectively. The profile of problem behaviour in the Chinese population with intellectual disability is consistent with the findings reported in the world literature. Antipsychotic drugs are the most commonly prescribed class of psychotropic medication used to treat such behaviours. Although the current evidence is not strong enough to support a clear‐cut recommendation on the use of medications, the dichotomous notion of ‘prescription’ or ‘no prescription’ for problem behaviours may be simplistic.
<p>Supplementary Materials and Methods, Figures and Tables</p>
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