The role of tRF-Val-CAC-010 in lung adenocarcinoma: implications for tumorigenesis and metastasis.

Transfer RNA-derived fragments (tRFs) are short non-coding RNA (ncRNA) sequences, ranging from 14 to 30 nucleotides, produced through the precise cleavage of precursor and mature tRNAs. While tRFs have been implicated in various diseases, including cancer, their role in lung adenocarcinoma (LUAD) remains underexplored. This study aims to investigate the impact of tRF-Val-CAC-010, a specific tRF molecule, on the phenotype of LUAD cells and its role in tumorigenesis and progression in vivo. The expression level of tRF-Val-CAC-010 was quantified using quantitative real-time polymerase chain reaction (qRT-PCR). Specific inhibitors and mimics of tRF-Val-CAC-010 were synthesized for transient transfection. Cell proliferation was assessed using the Cell Counting Kit-8 (CCK-8), while cell invasion and migration were evaluated through Transwell invasion and scratch assays. Flow cytometry was utilized to analyze cell cycle and apoptosis. The in vivo effects of tRF-Val-CAC-010 on tumor growth and metastasis were determined through tumor formation and metastasis imaging experiments in nude mice. The expression level of tRF-Val-CAC-010 was upregulated in A549 and PC9 LUAD cells (P < 0.01). Suppression of tRF-Val-CAC-010 expression resulted in decreased proliferation of A549 and PC9 cells (P < 0.001), reduced invasion and migration of A549 (P < 0.05, P < 0.001) and PC9 cells (P < 0.05, P < 0.01), enhanced apoptosis in both A549 (P < 0.05) and PC9 cells (P < 0.05), and increased G2 phase cell cycle arrest in A549 cells (P < 0.05). In vivo, the tumor formation volume in the tRF-inhibitor group was significantly smaller than that in the model and tRF-NC groups (P < 0.05). The metastatic tumor flux value in the tRF-inhibitor group was also significantly lower than that in the model and tRF-NC groups (P < 0.05). This study demonstrates that tRF-Val-CAC-010 promotes proliferation, migration, and invasion of LUAD cells and induces apoptosis in vitro, however, its specific effects on the cell cycle require further elucidation. Additionally, tRF-Val-CAC-010 enhances tumor formation and metastasis in vivo. Therefore, tRF-Val-CAC-010 may serve as a novel diagnostic biomarker and potential therapeutic target for LUAD.

Luo LL ，Cao Y ，Zhang JJ ，Xie YX ，Li L ，Yang H ，Long ZB ，Wang L ，Wang WP ... -  《BMC CANCER》

A pro-metastatic tRNA fragment drives aldolase A oligomerization to enhance aerobic glycolysis in lung adenocarcinoma.

Despite being the leading cause of lung cancer-related deaths, the underlying molecular mechanisms driving metastasis progression are still not fully understood. Transfer RNA-derived fragments (tRFs) have been implicated in various biological processes in cancer. However, the role of tRFs in lung adenocarcinoma (LUAD) remains unclear. Our study identified a tRF, tRF-Val-CAC-024, associated with the high-risk component of LUAD, through validation using 3 cohorts. Our findings demonstrated that tRF-Val-CAC-024 acts as an oncogene in LUAD. Mechanistically, tRF-Val-CAC-024 was revealed to bind to aldolase A (ALDOA) dependent on Q125/E224 and promote the oligomerization of ALDOA, resulting in increased enzyme activity and enhanced aerobic glycolysis in LUAD cells. Additionally, we provide preliminary evidence of its potential clinical value by investigating the therapeutic effects of tRF-Val-CAC-024 antagomir-loaded lipid nanoparticles (LNPs) in cell-line-derived xenograft models. These results could enhance our understanding of the regulatory mechanisms of tRFs in LUAD and provide a potential therapeutic target.

Wang Q ，Song X ，Zhang Y ，Liang S ，Zhang M ，Wang H ，Feng Y ，Li R ，Ding H ，Chen Y ，Xia W ，Dong G ，Xu L ，Mao Q ，Jiang F ... -  《Cell Reports》

Actin-like protein 8 promotes cell proliferation, colony-formation, proangiogenesis, migration and invasion in lung adenocarcinoma cells.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality worldwide of which lung adenocarcinoma (LUAD) is the most common. The identification of oncogenes and effective drug targets is the key to individualized LUAD treatment. Actin-like protein 8 (ACTL8), a member of the cancer/testis antigen family, is associated with tumor growth and patient prognosis in various types of cancer. However, whether ACTL8 is involved in the development of LUAD remains unknown. The aim of the present study was to demonstrate the role of ACTL8 in human LUAD cells. The expression of ACTL8 in LUAD tissues and cell lines was assessed using immunohistochemistry and western blotting. Additionally, plasmids expressing ACTL8-specific short hairpin RNAs were used to generate lentiviruses which were subsequently used to infect A549 and NCI-H1975 human LUAD cells. Cell proliferation, migration, invasion and apoptosis, as well as cell cycle progression and the expression of protein markers of epithelial to mesenchymal transition were investigated. A549 cell tumor growth in nude mice was also examined. The results showed that ACTL8 was highly expressed in A549 and NCI-H1975 LUAD cell lines. Additionally, ACTL8-knockdown inhibited proliferation, colony formation, cell cycle progression, migration and invasion, and increased apoptosis in both cell lines. Furthermore, in vivo experiments in nude mice revealed that ACTL8-knockdown inhibited A549 cell tumor growth. These results suggest that ACTL8 serves an oncogenic role in human LUAD cells, and that ACTL8 may represent a potential therapeutic target for LUAD. Our results suggest that ACTL8 serves an oncogenic role in human LUAD cells, and that ACTL8 may represent a potential therapeutic target for LUAD.

Ma S ，Wang X ，Zhang Z ，Liu D ... -  《-》

SGO2 as a Prognostic Biomarker Correlated with Cell Proliferation, Migration, Invasion, and Epithelial-Mesenchymal Transition in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is the predominant histological subtype among non-small cell lung cancer cases, representing approximately 40% of all cases. Shugoshin 2 (SGO2) is implicated in tumorigenesis and tumor progression. This study aimed to uncover a potential role of SGO2 in the LUAD. Data related to gene mRNA expression and clinical information were obtained from The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and the Cancer Cell Line Encyclopedia (CCLE) databases. Cell Counting Kit-8 (CCK-8), Transwell, scratch assay, and flow cytometry were applied to investigate the biological functions of SGO2 in the LUAD. Western blot was conducted to detect the protein expression. Through pan-cancer analysis, SGO2 was found to be consistently overexpressed in 25 of 33 cancer types, including LUAD. In vitro assays revealed that SGO2 knockdown significantly impeded cell proliferation, cell migration, invasion and epithelial-mesenchymal transition (EMT), whereas its overexpression promoted these abilities. Flow cytometry confirmed that SGO2 contributed to cell cycle progression and reduced cell apoptosis. Furthermore, SGO2 facilitated cell proliferation and regulated cell cycle through upregulating recombinant E2F transcription factor 1 (E2F1). Our study demonstrated that SGO2 was up-regulated in pan-cancers including LUAD and its high expression was strongly associated with poor overall survival (OS) and progression-free survival (PFS) of patients with LUAD. SGO2 promoted cell proliferation, cell migration, invasion and EMT of A549 cells. Additionally, E2F1 was involved in regulation of cell cycle and cell proliferation mediated by SGO2. This research elucidated the oncogenic significance of SGO2 in LUAD, proposing its potential as a prognostic biomarker and a promising target for therapeutic interventions.

Chen Y ，Xiang T 《-》

DUS4L suppresses invasion and metastasis in LUAD via modulation of PI3K/AKT and ERK/MAPK signaling through GRB2.

Limited research has focused on the role of dihydrouridine synthases (DUS) family members in human tumors. Our previous findings indicated an impact of dihydrouridine synthase 4 like (DUS4L) on cell proliferation and apoptosis in lung adenocarcinoma (LUAD) A549 cell, yet its broader functions and regulatory mechanisms in LUAD remain elusive. Using a LUAD tissue microarray and immunohistochemical (IHC) staining, we validated variations in DUS4L protein expression levels among LUAD patients and assessed its clinical significance. Additional experiments using short hairpin RNA (shRNA) against DUS4L (sh-DUS4L-2), LUAD cell lines, cell function assays (including wound healing, transwell migration and invasion, colony formation, and apoptosis assays), and mouse tumor xenografts were performed to examine the biological roles of DUS4L in LUAD progression. RNA sequencing, proteomic analyses, mass spectrometry, and co-immunoprecipitation experiments were conducted to identify and validate DUS4L-regulated downstream target genes and signaling pathways. We identified a consistent upregulation of DUS4L in LUAD tissues. In vitro and in vivo experiments underscored the inhibitory effect of DUS4L downregulation on LUAD progression, including migration, invasion, and proliferation. Mechanistically, DUS4L was found to interact with the signaling molecule GRB2, promoting LUAD progression and metastasis by inducing epithelial-mesenchymal transition (EMT) via the PI3K/AKT and ERK/MAPK pathways. Our results establish the functional role of DUS4L in driving the progression and metastasis of LUAD, implicating its potential as a candidate therapeutic target for LUAD.

Li Z ，Zhao PL ，Gao X ，Li X ，Meng YQ ，Li ZQ ，Zhai KR ，Wei SL ，Feng HM ，Huang HR ，Li B ... -  《-》