Identification of Tumor-Suppressive miR-139-3p-Regulated Genes: TRIP13 as a Therapeutic Target in Lung Adenocarcinoma.

Analyses of our microRNA (miRNA) expression signature combined with The Cancer Genome Atlas (TCGA) data revealed that both strands of pre-miR-139 (miR-139-5p, the guide strand, and miR-139-3p, the passenger strand) are significantly downregulated in lung adenocarcinoma (LUAD) clinical specimens. Functional analyses of LUAD cells ectopically expressing miR-139-3p showed significant suppression of their aggressiveness (e.g., cancer cell proliferation, migration, and invasion). The involvement of the passenger strand, miR-139-3p, in LUAD pathogenesis, is an interesting finding contributing to the elucidation of unknown molecular networks in LUAD. Of 1108 genes identified as miR-139-3p targets in LUAD cells, 21 were significantly upregulated in LUAD tissues according to TCGA analysis, and their high expression negatively affected the prognosis of LUAD patients. We focused on thyroid hormone receptor interactor 13 (TRIP13) and investigated its cancer-promoting functions in LUAD cells. Luciferase assays showed that miR-139-3p directly regulated TRIP13. siRNA-mediated TRIP13 knockdown and TRIP13 inhibition by a specific inhibitor (DCZ0415) attenuated the malignant transformation of LUAD cells. Interestingly, when used in combination with anticancer drugs (cisplatin and carboplatin), DCZ0415 exerted synergistic effects on cell proliferation suppression. Identifying the molecular pathways regulated by tumor-suppressive miRNAs (including passenger strands) may aid in the discovery of diagnostic markers and therapeutic targets for LUAD.

The Molecular Pathogenesis of Tumor-Suppressive miR-486-5p and miR-486-3p Target Genes: GINS4 Facilitates Aggressiveness in Lung Adenocarcinoma.

The involvement of passenger strands of miRNAs in the molecular pathogenesis of human cancers is a recent concept in miRNA research, and it will broaden our understanding of the molecular mechanisms of miRNA-mediated cancer. The analysis of our miRNA signature of LUAD revealed that both strands of pre-miR-486 (miR-486-5p and miR-486-3p) were downregulated in LUAD tissues. Ectopic expression of both miRNAs induced cell cycle arrest in LUAD cells, suggesting both strands of miRNAs derived from pre-miR-486 were tumor suppressive. Our in silico analysis showed a total of 99 genes may be under the control of both miRNAs in LUAD cells. Importantly, among these targets, the high expression of seven genes (MKI67, GINS4, RRM2, HELLS, MELK, TIMELESS, and SAPCD2) predicted a poorer prognosis of LUAD patients (p < 0.05). We focused on GINS4, a DNA replication complex GINS protein that plays an essential role in the initiation of DNA replication. Our functional assays showed that GINS4 was directly controlled by both strands of pre-miR-486, and its aberrant expression facilitated the aggressive behavior of LUAD cells. GINS4 is attractive as a therapeutic target for this disease. MiRNA analysis, including passenger strands, will further improve our understanding of the molecular pathogenesis of LUAD.

Minichromosome maintenance proteins in lung adenocarcinoma: Clinical significance and therapeutic targets.

Lung cancer is the most common cause of cancer-related death worldwide, accounting for 1.8 million deaths annually. Analysis of The Cancer Genome Atlas data showed that all members of the minichromosome maintenance (MCM) family (hexamers involved in DNA replication: MCM2-MCM7) were upregulated in lung adenocarcinoma (LUAD) tissues. High expression of MCM4 (P = 0.0032), MCM5 (P = 0.0032), and MCM7 (P = 0.0110) significantly predicted 5-year survival rates in patients with LUAD. Simurosertib (TAK-931) significantly suppressed the proliferation of LUAD cells by inhibiting cell division cycle 7-mediated MCM2 phosphorylation. This finding suggested that MCM2 might be a therapeutic target for LUAD. Moreover, analysis of the epigenetic regulation of MCM2 showed that miR-139-3p, miR-378a-5p, and miR-2110 modulated MCM2 expression in LUAD cells. In patients with LUAD, understanding the role of these miRNAs may improve prognoses.

Severe asthma remaining well-controlled after mepolizumab discontinuation: A case report and literature review.

Mepolizumab, a humanized anti-IL-5 monoclonal antibody used for severe asthma, results in a reduced rate of asthma exacerbation, improved lung function, reduced oral corticosteroid use, and improved quality of life. A 62-year-old man using high-dose inhaled corticosteroid visited our hospital because of poorly-controlled asthma. He had eosinophilia in peripheral blood and sputum, and high levels of fraction of exhaled nitric oxide. Therefore, he was treated with mepolizumab for severe asthma. Mepolizumab treatment resulted in significantly improved pulmonary function and reduced frequencies of asthma exacerbations. Because of his good asthma control, mepolizumab treatment was discontinued after 3 years. Since discontinuing mepolizumab, his asthma control has remained without exacerbation. Previous studies suggest that mepolizumab should be continued to sustain clinical benefits. However, cases of long-term controlled asthma have not been reported after mepolizumab withdrawal, and our case may be instructive.

MiR-15b-5p inhibits castration-resistant growth of prostate cancer cells by targeting the muscarinic cholinergic receptor CHRM3.

Cholinergic receptor muscarinic 3 (CHRM3)-mediated focal adhesion kinase/YES-associated protein (YAP) signalling is essential for the growth of castration-resistant prostate cancer (CRPC) cells. Here, we evaluated the molecular mechanisms through which CHRM3 overexpression facilitates castration-resistant growth. Small RNA sequencing combined with in silico analyses revealed that CHRM3 was a putative target of miR-15b-5p. Notably, androgen deprivation suppressed miR-15b-5p expression and increased CHRM3 expression. Moreover, miR-15b-5p bound directly to CHRM3 and inhibited YAP activation induced by CHRM3 stimulation. Furthermore, miR-15b-5p abolished the growth of CRPC cells induced by CHRM3 stimulation. We conclude that the miR-15b-5p/CHRM3/YAP signalling axis promotes the castration-resistant growth of prostate cancer.

[Therapeutic Strategies for Metachronous Multiple Primary Lung Cancer].

BACKGROUNDS: It is not uncommon to encounter metachronous primary lung cancer after surgical treatment along with the increase in the elderly patients. In consideration of increasing number of such patients, it is necessary to take various treatment strategies. METHODS: In order to establish a treatment strategy for multiple lung cancer, we retrospectively examined multiple lung cancer cases operated for primary lung cancer in our department from January 2013 to December 2019, and the future treatment strategy was examined. RESULTS: Of 821 patients who underwent surgery for primary lung cancer, 61 were multiple lung cancers, 31 were synchronous multiple lung cancers, and 30 were metachronous multiple lung cancers. Among the cases of metachronous multiple lung cancer, 28 cases had undergone lobectomy or more in the first operation, 1 case of segmental resection, and 1 case of partial resection. As for the treatment of secondary lung cancer lesions, 21 lesions were performed surgery( lobectomy;2, segmental resection;2, partial resection;17), 6 lesions of photodynamic therapy (PDT), and 3 lesions of stereotactic body radiation therapy (SBRT). Among the surgical cases, there were three cases on the same side as the first cancer and 18 cases on the opposite side. The three cases underwent partial resection. Among 21 patients, postoperative home oxygen therapy was introduced in 2 patients. Regarding the prognosis, three patients who had surgical resection, died of recurrence of the first lesion. One of the six PDT patients died of recurrence of the first lung cancer and another died of other disease. All three patients who underwent SBRT are alive without recurrence. CONCLUSIONS: If early detection and early diagnosis are made as a treatment strategy for metachronous multiple lung cancer, it may be possible to preserve lung function by reducing surgery or SBRT, PDT, and to cure without damaging the quality of life.