Two somatic mutations in the androgen receptor N-terminal domain are oncogenic drivers in hepatocellular carcinoma.

The androgen receptor (AR) plays an important role in male-dominant hepatocellular carcinoma, and specific acquired somatic mutations of AR have been observed in HCC patients. Our previous research have established the role of AR wild type as one of the key oncogenes in hepatocarcinogenesis. However, the role of hepatic acquired somatic mutations of AR remains unknown. In this study, we identify two crucial acquired somatic mutations, Q62L and E81Q, situated close to the N-terminal activation function domain-1 of AR. These mutations lead to constitutive activation of AR, both independently and synergistically with androgens, making them potent driver oncogene mutations. Mechanistically, these N-terminal AR somatic mutations enhance de novo lipogenesis by activating sterol regulatory element-binding protein-1 and promote glycogen accumulation through glycogen phosphorylase, brain form, thereby disrupting the AMPK pathway and contributing to tumorigenesis. Moreover, the AR mutations show sensitivity to the AMPK activator A769662. Overall, this study establishes the role of these N- terminal hepatic mutations of AR as highly malignant oncogenic drivers in hepatocarcinogenesis and highlights their potential as therapeutic targets for patients harboring these somatic mutations.

Variations in pleural microbiota and metabolic phenotype associated with malignant pleural effusion in human lung adenocarcinoma.

BACKGROUND: Lung cancer is the most common cancer-related death worldwide. In 2022, the number of daily deaths of lung cancer was estimated to reach around 350 in the United States. Lung adenocarcinoma is the main subtype of lung cancer and patients with malignant pleural effusion (MPE) suffer from poor prognosis. Microbiota and its metabolites are associated with cancer progression. However, the effect of pleural microbiota on pleural metabolic profile of MPE in lung adenocarcinoma patients remains largely unknown. METHODS: Pleural effusion samples collected from lung adenocarcinoma patients with MPE (n = 14) and tuberculosis pleurisy patients with benign pleural effusion (BPE group, n = 10) were subjected to microbiome (16S rRNA gene sequencing) and metabolome (liquid chromatography tandem mass spectrometry [LC-MS/MS]) analyses. The datasets were analyzed individually and integrated for combined analysis using various bioinformatic approaches. RESULTS: The metabolic profile of MPE in lung adenocarcinoma patients were clearly distinguished from BPE with 121 differential metabolites across six significantly enriched pathways identified. Glycerophospholipids, fatty and carboxylic acids, and derivatives were the most common differential metabolites. Sequencing of microbial data revealed nine significantly enriched genera (i.e., Staphylococcus, Streptococcus, Lactobacillus) and 26 enriched ASVs (i.e., species Lactobacillus_delbrueckii) in MPE. Integrated analysis correlated MPE-associated microbes with metabolites, such as phosphatidylcholine and metabolites involved in the citrate cycle pathway. CONCLUSION: Our results provide substantial evidence of a novel interplay between the pleural microbiota and metabolome, which was drastically perturbed in MPE in lung adenocarcinoma patients. Microbe-associated metabolites can be used for further therapeutic explorations.

High expression of TMEM40 contributes to progressive features of tongue squamous cell carcinoma.

Transmembrane protein 40 (TMEM40) is a 23­kDa protein and its association with tongue squamous cell carcinoma (TSCC) remains unclear. This study aimed to investigate the expression and clinical significance of TMEM40 in TSCC and its roles in TSCC cells. Immunohistochemical analysis was performed to detect the expression levels of TMEM40 in 60 tongue tissue samples. Furthermore, TMEM40 was overexpressed and inhibited in two TSCC cell lines by transfection with pEZ­M98­TMEM40 plasmid or TMEM40 small interfering RNA, respectively. Cell Counting Kit­8 and colony formation assays were used to investigate the effects of TMEM40 on cell proliferation and colony formation ability, respectively. Flow cytometry was performed to determine cell apoptosis and cycle conditions of transfected cells. Wound­healing and Transwell assays were processed to explore the effects of TMEM40 on cell migration and invasion, respectively. The results indicated that TMEM40 expression levels were significantly increased in TSCC tissues compared with adjacent normal tongue tissues (P<0.01). Clinicopathological analysis revealed that TMEM40 expression was positively correlated with pathological TNM (pTNM) status (P<0.05), histological grade (P<0.001) and clinical stage (P<0.01), but not with sex or age. Results of cell proliferation, apoptosis, migration and invasion assays indicated that when TMEM40 had been successfully overexpressed or knocked down in CAL27 and SCC9 TSCC cell lines, cell growth and invasion increased in the TMEM40 overexpressing cells, while they decreased in TMEM40­knockdown cells. Furthermore, experiments revealed that TMEM40 knockdown resulted in increased levels of p53 and Bax, and decreased levels of MMP­9, which indicated that TMEM40 regulated cell apoptosis and migration via involvement of p53, Bax and MMP­9 in TSCC cells. Our findings indicated that increased expression of TMEM40 contributed to progressive features of TSCC via regulation of p53, Bax and MMP­9.

The characterization of lung microbiome in lung cancer patients with different clinicopathology.

There were few knowledge concerned correlation between lung microbiome and different clinicopathology of lung cancer. Bronchial washing fluid (BWF) and sputum are commonly used sample types but there was no study comparing difference of microbiome between these two in lung cancer. In this study, we aimed to compare difference of microbiome between these two sample types and characterize lung microbiome in squamous cell lung carcinoma with (SCC_M1) or without distant metastasis (SCC_M0) and lung adenocarcinoma with (AD_M1) or without distant metastasis (AD_M0). We collected 40 BWF samples and 52 sputum samples from newly diagnosed lung cancer patients. Bacterial species were sequenced via 16S rRNA sequencing. Phylum Proteobacteria in BWF samples were significantly higher than sputum samples (Wilcoxon test, P = 0.003). At phylum level, microbiome of BWF samples was more similar to that of lung cancer tissues reported in the previous literature. LEFse analysis showed that in BWF group, genera Veillonell, Megasphaera, Actinomyces and Arthrobacter in AD_M0 were significantly higher than those in SCC_M0, and genera Capnocytophaga and Rothia in AD_M1 were significantly lower than that in SCC_M1. Compared with AD_M0, genus Streptococcus of AD_M1 was significantly lower, and genera Veillonella and Rothia in SCC_M1 were significantly higher than that in SCC_M1. Our study suggested that BWF samples might better reflect the microbiome of lung cancer tissues. In different metastatic states of lung cancer, differential genera between squamous cell carcinoma and adenocarcinoma were different. And in different histologic types of lung cancer, distant metastasis-related genera were not the same.

Prognostic role of systemic immune-inflammation index in solid tumors: a systematic review and meta-analysis.

BACKGROUND: Inflammation may play an important role in cancer progression, and a higher systemic immune-inflammation index (SII) has been reported to be a poor prognostic marker in several malignancies. However, the results of published studies are inconsistent. MATERIALS AND METHODS: A systematic review of databases was conducted to search for publications regarding the association between blood SII and clinical outcome in solid tumors with a date up to February 12, 2017. The primary outcome was overall survival (OS) and the secondary outcomes were progression-free survival (PFS) and cancer-specific survival (CSS). Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were used to assess the strength of the association between blood SII and clinical outcome in solid tumors. RESULTS: A total of 15 articles were included in the analysis. Overall, systemic immune-inflammation index greater than the cutoff predicted poor overall survival (HR = 1.55, 95% CI = 1.27-1.88; P < 0.001). Subgroup analyses revealed that high systemic immune-inflammation index indicated a worse overall survival in hepatocellular carcinoma (P < 0.001), urinary cancers (P < 0.001), gastrointestinal tract cancers (P = 0.02), small cell lung cancer (P < 0.05) and acral melanoma (P < 0.001). Hazard ratio for systemic immune-inflammation index greater than the cutoff for cancer-specific survival was 1.44 (P < 0.05). CONCLUSIONS: Elevated systemic immune-inflammation index is associated with a worse overall survival in many solid tumors. The systemic-inflammation index can act as a powerful prognostic indicator of poor outcome in patients with solid tumors.

Association between vascular endothelial growth factor +936C/T polymorphism and breast cancer risk: a meta-analysis of 18 case-control studies.

Important in angiogenesis, vascular endothelial growth factor (VEGF) acts as a biomarker in the growth of and prognosis for breast cancer. Evidence suggests that single nucleotide polymorphisms of VEGF such as +936C/T (rs3025039) effects VEGF levels; however, current studies on the association between +936C/T and breast cancer risk are inconsistent. This meta-analysis was conducted to reach a more precise conclusion about this association. PubMed was searched for case-control studies on the association between +936C/T levels and breast cancer risk. The quality of each study was scoring in term of some important criteria. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of this association. Subgroup analysis stratified by ethnicity and quality score was also conducted. Eighteen studies with 10,694 cases and 11,199 controls in accord with the selection criteria were included in our meta-analysis. When all eligible studies were pooled, our meta-analysis showed that there was no significant association between +936C/T and breast cancer risk in the all ethnic group; however, in the subgroup analysis, we found that +936C/T was associated with reduced breast cancer risk in the Asian population. When stratified by the quality score, no significant association was found between +936C/T and breast cancer risk either in studies scored <8 or studies scored >7. Our findings suggested that +936C/T is not associated with breast cancer risk but may reduce the risk in the Asian population.