The importance of mRNA N6‐methyladenosine (m⁶A) modification during tumor metastasis is controversial as it plays distinct roles in different biological contexts. Moreover, how cancer cell plasticity is shaped by m⁶A modification is interesting but remains uncharacterized. Here, this work shows that m⁶A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) is remarkably upregulated in metastatic lung adenocarcinoma (LUAD) and indicates worse prognosis of patients. Interestingly, IGF2BP3 induces partial epithelial‐mesenchymal‐transition (EMT) and confers LUAD cells plasticity to metastasize through m⁶A‐dependent overactivation of Notch signaling. Mechanistically, IGF2BP3 recognized m⁶A‐modified minichromosome maintenance complex component (MCM5) mRNAs to prolong stability of them, subsequently upregulating MCM5 protein, which competitively inhibits SIRT1‐mediated deacetylation of Notch1 intracellular domain (NICD1), stabilizes NICD1 protein and contributes to m⁶A‐dependent IGF2BP3‐mediated cellular plasticity. Notably, a tight correlation of the IGF2BP3/MCM5/Notch axis is evidenced in clinical LUAD specimens. Therefore, this study elucidates a critical role of m⁶A modification on LUAD cell plasticity in fostering tumor metastasis via the above axis, providing potential targets for metastatic LUAD.

Background: The prognosis of human glioma is poor, and the highly invasive nature of the disease represents a major impediment to current therapeutic modalities. The oncoprotein B-cell-specific Moloney murine leukemia virus integration site 1 protein (Bmi-1) has been linked to the development and progression of glioma; however, the biological role of Bmi-1 in the invasion of glioma remains unclear. Methods: A172 and LN229 glioma cells were engineered to overexpress Bmi-1 via stable transfection or to be silenced for Bmi-1 expression using RNA interfering method. Migration and invasiveness of the engineered cells were assessed using wound healing assay, Transwell migration assay, Transwell matrix penetration assay and 3-D spheroid invasion assay. MMP-9 expression and activity were measured using real-time PCR, ELISA and the gelatin zymography methods. Expression of NF-kappaB target genes was quantified using real-time PCR. NF-kappaB transcriptional activity was assessed using an NF-kappaB luciferase reporter system. Expression of Bmi-1 and MMP-9 in clinical specimens was analyzed using immunohistochemical assay. Results: Ectopic overexpression of Bmi-1 dramatically increased, whereas knockdown of endogenous Bmi-1 reduced, the invasiveness and migration of glioma cells. NF-kappaB transcriptional activity and MMP-9 expression and activity were significantly increased in Bmi-1-overexpressing but reduced in Bmi-1-silenced cells. The reporter luciferase activity driven by MMP-9 promoter in Bmi-1-overexpressing cells was dependent on the presence of a functional NF-kappaB binding site, and blockade of NF-kappaB signaling inhibited the upregulation of MMP-9 in Bmi-1 overexpressing cells. Furthermore, expression of Bmi-1 correlated with NF-kappaB nuclear translocation as well as MMP-9 expression in clinical glioma samples. Conclusions: Bmi-1 may play an important role in the development of aggressive phenotype of glioma via activating the NF-kappaB/MMP-9 pathway and therefore might represent a novel therapeutic target for glioma.

Aberrant activation of EGFR represents a common event in non-small cell lung carcinoma (NSCLC) and activates various downstream signaling pathways. While EGFR activation of β-catenin signaling was previously reported, the mediating mechanism remains unclear. Our current study found that EGFR activation in NSCLC cells releases SHC-binging protein 1 (SHCBP1) from SHC adaptor protein 1 (SHC1), which subsequently translocates into the nucleus and directly promotes the transactivating activity of β-catenin, consequently resulting in development of NSCLC cell stemness and malignant progression. Furthermore, SHCBP1 promotes β-catenin activity through enhancing the CBP/β-catenin interaction, and most interestingly, a candidate drug that blocks the CBP/β-catenin binding effectively abrogates the aforementioned biological effects of SHCBP1. Clinically, SHCBP1 level in NSCLC tumors was found to inversely correlate with patient survival. Together, our study establishes a novel convergence between EGFR and β-catenin pathways and highlights a potential significance of SHCBP1 as a prognostic biomarker and a therapeutic target.

Glioma represents a serious health problem worldwide. Despite advances in surgery, radiotherapy, chemotherapy, and targeting therapy, the disease remains one of the most lethal malignancies in humans, and new approaches to improvement of the efficacy of anti-glioma treatments are urgently needed. Thus, new therapeutic targets and tools should be developed based on a better understanding of the molecular pathogenesis of glioma. In this context, microRNAs (miRNAs), a class of small, non-coding RNAs, play a pivotal role in the development of the malignant phenotype of glioma cells, including cell survival, proliferation, differentiation, tumor angiogenesis, and stem cell generation. This review will discuss the biological functions of miRNAs in human glioma and their implications in improving clinical diagnosis, prediction of prognosis, and anti-glioma therapy.

Non-small cell lung cancer (NSCLC) is the most commonly diagnosed and fatal cancer worldwide. Sclerostin domain containing protein 1 (SOSTDC1) has been found to be tumor-suppressive in several types of cancers. However, the expression level and biological functions of SOSTDC1 in NSCLC remain unknown. Our current study aimed to identify the biological significance of SOSTDC1 in NSCLC. We found that SOSTDC1 was significantly down-regulated in NSCLC. Moreover, patients with higher expression of SOSTDC1 had a significant better prognosis than those with lower SOSTDC1 expression. Ectopic expression of SOSTDC1 in NSCLC cell lines A549 and NCI-H520 could inhibit proliferation as shown by MTT, colony formation, soft agar and EdU incorporation assays in vitro. Furthermore, A549 cells stably expressing ectopic SOSTDC1 grew more slowly and formed smaller tumors than vector-control cells in vivo. Mechanistic studies demonstrated that SOSTDC1 over-expression led to increased p21Cip and p27Kip levels, thereby decreasing Rb phosphorylation status and E2F transcription activity. SOSTDC1 is down-regulated in NSCLC, and its expression level is indicative of clinical outcome of patients with the disease. SOSTDC1 might represent a tumor suppressor through inhibiting the proliferation of NSCLC cells by regulating p21Cip and p27Kip, which in turn affects Rb-E2F signaling.

Metastasis accounts for 90% of cancer-related deaths and represents a prominent malignant feature in non-small cell lung cancer (NSCLC), while tumor cell-specific mechanisms and molecules pivotal for the metastatic capacity remain unclear. By analyzing single-cell RNA sequencing data, we found that fatty acid binding protein 7 (FABP7) was specifically up-regulated in tumor cells of metastatic NSCLC patients and might be a prognostic indicator for poor survival. Experimental studies based on NSCLC cell lines showed that FABP7 promoted the metastatic competencies of NSCLC cells in vitro and in vivo. Mechanistically, we demonstrated that FABP7 was important to canonical Wnt signaling activation and competitively inhibited the interaction between β-catenin and components of its cytoplasmic degradation complex, thereby repressing the phosphorylation-dependent ubiquitination and degradation of β-catenin. Our present study identifies FABP7 as a metastatic tumor cell-specific pro-metastatic gene and uncovers a previously unknown regulatory mechanism underlying Wnt hyperactivation via FABP7-impaired cytoplasmic β-catenin degradation, implicating a novel molecule in regulating NSCLC metastasis.