Upregulation of M6A Reader HNRNPA2B1 Associated with Poor Prognosis and Tumor Progression in Lung Adenocarcinoma.

Lung cancer is the most prevalent malignancy worldwide, and lung adenocarcinoma (LUAD) accounts for a substantial proportion of all cases. N6-methyladenosine (m6A) is the most frequent post-transcriptional modification in mRNAs that also plays a role in cancer development. Heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) is a reader of m6A modification, which can affect tumor invasion, migration, and proliferation. The purpose of this study was to explore the prognostic factors of LUAD based on m6A through bioinformatics analysis. The expression levels and prognostic significance of HNRNPA2B1 in LUAD were analyzed on the basis of data extracted from the UALCAN, GEPIA, NCBI-GEO, Human Protein Atlas, STRING, miRDB, TargetScan, PROMO, Starbase, UCSC Xena browser, TIMER, and TISIDB databases. HNRNPA2B1 protein and mRNA levels in several LUAD cell lines were detected by western blotting and qRT-PCR. CCK8, wound-healing and transwell assays were performed to evaluate the proliferation, invasion, and migration abilities of LUAD cells. HNRNPA2B1 mRNA was found to be significantly overexpressed in LUAD tissues, and its high levels correlated with poor OS and DFS. The genes co-expressed with HNRNPA2B1 were related to mRNA production, cell cycle, and histone binding. To determine the mechanistic basis of HNRNPA2B1 in LUAD, we next predicted the microRNAs and transcription factors that were directly associated with HNRNPA2B1, as well as copy number changes. In addition, it was found that HNRNPA2B1 expression was significantly related to CD4+ T cells, neutrophils, lymphocytes, immunomodulators, and chemokines. Besides, knocking down HNRNPA2B1 in the LUAD cells led to a significant reduction in their proliferation, invasion, and migration rates in vitro. Elevated HNRNPA2B1 is a risk factor in LUAD and portends a poor prognosis.

Wang W ，Li S 《-》

HNRNPA2B1 inhibited SFRP2 and activated Wnt-β/catenin via m6A-mediated miR-106b-5p processing to aggravate stemness in lung adenocarcinoma.

Cancer stem cells (CSCs) exhibit strong self-renewal capability to contribute to tumorigenesis in lung adenocarcinoma (LUAD). N6-methyladenosine (m6A) methylation is confirmed as a key mechanism for stemness acquisition and tumor growth. Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) is a known m6A reader and is reported to participate in LUAD progression, but its relation with stemness of LUAD cells is unknown. Thus, this study aimed to uncover the effect of HNRNPA2B1 in stemness of LUAD cells. The association of HNRNPA2B1 with LUAD prognosis was analyzed via Gene Expression Profiling Interactive Analysis (GEPIA). Sphere formation, cytometry flow analysis and western blot of stemness-related genes were performed to examine the stemness of LUAD cells. m6A modification was investigated by RNA immunoprecipitation. Results depicted that HNRNPA2B1 was upregulated in LUAD CSCs. HNRNPA2B1 knockdown repressed cell stemness, proliferation, migration, and tumor growth of LUAD. As to mechanism, HNRNPA2B1 read the m6A site on primary microRNA-106b (pri-miR-106b) to facilitate the maturing of miR-106b-5p, so that miR-106b-5p targeted secreted frizzled-related protein 2 (SFRP2), activating Wnt/β-catenin signaling. In conclusion, HNRNPA2B1 inhibits SFRP2 and activates Wnt-β/catenin via m6A-mediated maturing of miR-106b-5p to aggravate stemness and LUAD progression, which potentially offered HNRNPA2B1 as a potential marker in CSCs-targeted treatment for LUAD.

Rong L ，Xu Y ，Zhang K ，Jin L ，Liu X ... -  《-》

KIAA1429 promotes the progression of lung adenocarcinoma by regulating the m6A level of MUC3A.

Lung adenocarcinoma (LUAD) is one of the most frequently occurring human malignancies worldwide, but its potential molecular mechanism has not yet been fully elucidated. N6-methyladenosine (m6A), the most common internal chemical modification of mRNAs, is implicated in diverse pathological processes in different human malignancies, but its functions in LUAD remain elusive. The current study aimed to investigate the function and molecular mechanism of KIAA1429 in LUAD. The KIAA1429 expression level in LUAD tissues was assessed using databases and was detected in LUAD cells and tissues via quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot. m6A levels in LUAD tissues and cells were quantified. Next, correlation between the KIAA1429 expression level and the clinical and pathological features and prognosis of patients with LUAD was analyzed. Further, KIAA1429 levels were decreased, and LUAD cell proliferation, migration, invasion, and cycle were assessed. Prediction websites revealed the aberrant expression and probable methylation modification of MUC3A in LUAD, and correlation between MUC3A and KIAA1429 was analyzed. Ultimately, the impact of the KIAA1429 expression on MUC3A-mediated malignant phenotypes of LUAD was examined by a torsion test. KIAA1429 expression was remarkably high and m6A level was aberrantly elevated in LUAD cells and tissues. In addition, high KIAA1429 expression indicated a larger tumor diameter, higher tumor-node-metastasis stage, greater proneness to lymph node and distant metastasis, and lower overall survival rate. siRNA-triggered KIAA1429 downregulation dramatically suppressed LUAD cell proliferation, migration, invasion, and cell cycle arrest in the G1 phase. Bioinformatics analysis revealed that MUC3A was expressed in LUAD at an unusually high level and may be methylated under the control of KIAA1429. Western blot, qRT-PCR, and correlation analyses revealed a positive correlation between KIAA1429 expression level and MUC3A. Finally, torsion test results revealed that low KIAA1429 expression reversed LUAD cell migration, proliferation, and invasion facilitated by low MUC3A expression as well as cell cycle arrest in the G1 phase. KIAA1429 exhibited an unusually high expression in LUAD cells and tissues, and high KIAA1429 expression was correlated with the clinical and pathological features of patients with LUAD, thereby leading to an unsatisfactory prognosis. Furthermore, KIAA1429 regulates MUC3A expression through m6A modification to modulate LUAD cells to proliferate, migrate, invade, and induce cell cycle arrest.

Zhao W ，Xie Y 《-》

Expression and Prognostic Significance of m6A-Related Genes in Lung Adenocarcinoma.

Zhang Y ，Liu X ，Liu L ，Li J ，Hu Q ，Sun R ... -  《MEDICAL SCIENCE MONITOR》

KIAA1429 Induces m6A Modification of LINC01106 to Enhance the Malignancy of Lung Adenocarcinoma Cells via the JAK/STAT3 Pathway.

Xu D ，Wang Z ，Li F 《CRITICAL REVIEWS IN IMMUNOLOGY》