METTL14 regulates CD8+T-cell activation and immune responses to anti-PD-1 therapy in lung cancer.

BACKGROUND: N6-methyladenosine (m6A) modification plays an important role in lung cancer. However, methyltransferase-like 14 (METTL14), which serves as the main component of the m6A complex, has been less reported to be involved in the immune microenvironment of lung cancer. This study aimed to analyze the relationship between METTL14 and the immune checkpoint inhibitor programmed death receptor 1 (PD-1) in lung cancer. METHODS: CCK-8, colony formation, transwell, wound healing, and flow cytometry assays were performed to explore the role of METTL14 in lung cancer progression in vitro. Furthermore, syngeneic model mice were treated with sh-METTL14 andan anti-PD-1 antibody to observe the effect of METTL14 on immunotherapy. Flow cytometry and immunohistochemical (IHC) staining were used to detect CD8 expression. RIP and MeRIP were performed to assess the relationship between METTL14 and HSD17B6. LLC cells and activated mouse PBMCs were cocultured in vitro to mimic immune cell infiltration in the tumor microenvironment. ELISA was used to detect IFN-γ and TNF-α levels. RESULTS: The online database GEPIA showed that high METTL14 expression indicated a poor prognosis in patients with lung cancer. In vitro assays suggested that METTL14 knockdown suppressed lung cancer progression. In vivo assays revealed that METTL14 knockdown inhibited tumor growth and enhanced the response to PD-1 immunotherapy. Furthermore, METTL14 knockdown enhanced CD8+T-cell activation and infiltration. More importantly, METTL14 knockdown increased the stability of HSD17B6 mRNA by reducing its m6A methylation. In addition, HSD17B6 overexpression promoted the activation of CD8+ T cells. CONCLUSION: The disruption of METTL14 contributed to CD8+T-cell activation and the immunotherapy response to PD-1 via m6A modification of HSD17B6, thereby suppressing lung cancer progression.

Hyperthermia promotes exosome secretion by regulating Rab7b while increasing drug sensitivity in adriamycin-resistant breast cancer.

PURPOSE: To investigate the mechanism through which hyperthermia promotes exosome secretion and drug sensitivity in adriamycin-resistant breast cancer. MATERIALS AND METHODS: We first evaluated the effect of hyperthermia on adriamycin-resistant breast cancer viability and used transmission electron microscopy, nanoparticle tracking analysis, and a bicinchoninic acid kit to validate the effect of hyperthermia on exosome secretion. The effective targeting molecules and pathways changed by hyperthermia were explored by RNA microarray and verified in vitro. The adriamycin-resistant MCF-7/ADR cells co-incubated with the exosomes produced by MCF-7/ADR cells after hyperthermia were assessed. The uptake of exosomes by MCF-7/ADR cells after hyperthermia treatment was evaluated by confocal microscopy. Finally, the mechanism through which hyperthermia promotes exosome secretion by hyperthermia was determined. RESULTS: Hyperthermia significantly suppressed the growth of adriamycin-resistant breast cancer cells and increased drug sensitivity by upregulating FOS and CREB5, genes related to longer overall survival in breast cancer patients. Moreover, hyperthermia promoted exosome secretion through Rab7b, a small GTPase that controls endosome transport. The upregulated FOS and CREB5 antioncogenes can be transferred to MCF-7/ADR cells by hyperthermia-treated MCF-7/ADR cell-secreted exosomes. CONCLUSIONS: Our results demonstrated a novel function of hyperthermia in promoting exosome secretion in adriamycin-resistant breast cancer cells and revealed the effects of hyperthermia on tumor cell biology. These hyperthermia-triggered exosomes can carry antitumor genes to the residual tumor and tumor microenvironment, which may be more beneficial to the effects of hyperthermia. These results represent an exploration of the relationship between therapeutic strategies and exosome biology.

Coexistence of a novel NBEA-ALK, EML4-ALK double-fusion in a lung adenocarcinoma patient and response to alectinib: A case report.

OBJECTIVES: The echinoderm microtubule-associated protein-like 4 gene (EML4) and anaplastic lymphoma kinase gene (ALK) fusion is the most common ALK rearrangements in non-small cell lung cancer (NSCLC). Herein, we firstly report that coexistence of a novel Neurobeachin (NBEA)-ALK, EML4-ALK double-fusion is sensitive to alectinib. MATERIALS AND METHODS: Hematoxylin-eosin staining (HE), fluorescent in situ hybridization (FISH), and next-generation sequencing (NGS) was performed on the biopsy sample. RESULTS: The patient responded to alectinib as a second-line treatment and achieved stable disease for 11 months, without significant symptoms of toxicity. Significantly, the liquid biopsy also validated clinical benefit, with the disappearance of NBEA-ALK and EML4-ALK fusion variants. We also provided a comprehensive review of all 50 ALK fusion genes in NSCLC. CONCLUSION: This is the first report on one patient with a novel NBEA-ALK, EML4-ALK double-ALK fusion beneficial from alectinib. Alectinib may be a viable therapeutic option for NSCLC patients with double-ALK fusion, and liquid biopsy could dynamically monitor clinical curative effect.

Exosomal miR-222 from adriamycin-resistant MCF-7 breast cancer cells promote macrophages M2 polarization via PTEN/Akt to induce tumor progression.

Exosome-mediated intercellular communication is considered to be an effective mode for malignant cells to transform biological behaviors in stromal cells. However, the mechanisms by which exosomes modulate macrophages within tumor microenvironment remain largely unclear. In this study, we found that both adriamycin-resistant breast cancer (BCa) cells and the corresponding exosomes (A/exo) were capable of inducing macrophages M2 polarization, which promoted the mobility, proliferation, migration and invasion of BCa cells. Since exosomes deliver microRNAs to affect cellular functions in recipient cells, we confirmed that miR-222 was significantly enriched in A/exo and could be successfully transferred to macrophages. Increased miR-222 level was also detected in exosomes derived from plasma and tissues of chemoresistant patients. Moreover, exosomal miR-222 from A/exo polarized M2 macrophages by targeting PTEN and activating Akt signaling pathway, which promoted BCa cells progression in a feed back loop. Co-culture of adriamycin-resistant BCa cells with macrophages in which miR-222 was upregulated or treated with A/exo facilitated tumor growth in vivo. Collectively, our data demonstrated that chemoresistant BCa cells could remodel macrophages within tumor microenvironment by secreting exosomal miR-222, which directly targeted PTEN and caused Akt cascade activation and macrophages M2 polarization. Our findings may provide a foundation for a promising strategy of BCa treatment by targeting exosomes or exosomal miR-222.

Sex disparities in cancer.

Sex is a key biological factor affecting the development of many cancer types. There are considerable differences between male and female subpopulations in terms of cancer incidence, prognosis and mortality. Recent studies have extensively characterized the sex-biased molecular changes in cancer patients. Further efforts should be made to develop sex-specific cancer prevention and therapeutic strategies.

The long noncoding RNA urothelial carcinoma-associated 1 overexpression as a poor prognostic biomarker in clear cell renal cell carcinoma.

Long noncoding RNA urothelial carcinoma-associated 1 has previously played important roles in cancer. However, its role is still unknown in clear cell renal cell carcinoma. We utilized the most recent molecular and clinical data of clear cell renal cell carcinoma from The Cancer Genome Atlas project, and the relationship between urothelial carcinoma-associated 1 expression and the clinicopathological features was analyzed. Our results indicated that urothelial carcinoma-associated 1 overexpression was associated with male ( p = 0.003), wild-type PBRM1 ( p = 0.021), and BAP1 mutation ( p = 0.022) in clear cell renal cell carcinoma, although lower expression was found in tumors compared with normal controls, validated in tumor tissues from The Cancer Genome Atlas and 21 clear cell renal cell carcinoma patients at our hospital. Moreover, urothelial carcinoma-associated 1 overexpression indicated poor prognosis independently (Hazard Ratio [HR]: 1.92, p = 0.000) in clear cell renal cell carcinoma; it might be a potential detrimental gene considered as a predictive biomarker involved in clear cell renal cell carcinoma.

The Role of FGFR1 Gene Amplification as a Poor Prognostic Factor in Squamous Cell Lung Cancer: A Meta-Analysis of Published Data.

OBJECTIVES: The prognostic factors of the fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) remain controversial. METHODS: We conducted a meta-analysis of published studies from 1974 to February 2015. In absence of quality difference between studies of reporting significant and nonsignificant results, the relationship between FGFR1 amplification and clinicopathological parameters in NSCLC was analyzed. And also the combined hazard ratio (HR) and their corresponding 95% confidence interval (CI) were calculated in terms of overall survival. RESULTS: 3178 patients (12 studies) were included in the analysis. It was shown that FGFR1 amplification was significantly more prevalent among male patients (RR 2.03, 95% CI 1.57-2.63) with squamous cell lung cancer (SQCC) (RR 3.49, 95% CI 2.62-4.64) and current smokers (RR 2.63, 95% CI 1.92-3.60). The pooled data also showed that the FGFR1 amplification was a poor prognostic factor in SQCC (HR 1.38, 95% CI 1.07-1.78), Asian patients (HR 1.78, 95% CI 1.22-2.60), and fluorescence in situ hybridization (FISH) method (HR 1.30, 95% CI 1.06-1.58). CONCLUSIONS: This meta-analysis strongly suggests that FGFR1 amplification occurs more frequently in male, SQCC and smokers, and it is a risk factor for poor prognosis among Asian patients with SQCC.