Selected Articles from This Issue

Bone metastasis is a commonly observed phenomenon in prostate cancer patients and is the primary cause of death. Despite the prominent osteoblastic nature of bone-metastatic prostate cancer, targeted therapeutics aimed at bone-metastatic prostate cancer are mainly focused on inhibition of osteolysis. In their study, Johnson and colleagues aimed to elucidate the significance of bone-metastatic prostate cancer-induced mesenchymal stem cell (MSC) CXCL8 expression on osteogenesis. The authors performed Alizarin Red and alkaline phosphatase assays on murine CRISPR-Cas9 Cxcl1 (murine homolog of CXCL8) knockout MSCs to evaluate its role in osteoblastogenesis and found enhanced calcium deposits and increased alkaline phosphatase activity in Cxcl1 knockout MSCs compared to control MSCs. The expression of osteoblastic transcription factors RUNX2 and OSX were differentially altered in murine Cxcl1 knockout MSCs and human bone marrow CXCL8 knockdown MSCs, suggesting a regulatory role of CXCL8 in MSC differentiation. RNA sequencing and subsequent analysis of differentially expressed genes using GO enrichment and GSEA for Cxcl1 knockout MSCs showed altered enrichment of genes associated with extracellular matrix remodeling, steroid metabolism, and immune activation. Ex vivo tibias derived from in vivo bone metastasis studies using intratibial injection of murine Cxcl1 knockout MSCs, revealed increased Trichrome staining in Cxcl1 knockout MSC tumors compared to the control. Although CXCL1 blockade increased MSC osteogenesis, Cxcl1 knockout MSCs significantly suppressed tumor growth and altered neutrophil phenotypes in vivo. Overall, this study demonstrates the regulatory function of CXCL1 in osteogenesis and the bone microenvironment and proposes its potential as a therapeutic target in bone-metastatic prostate cancer.Pseudogene-derived lncRNA SFTA1P has recently been linked with the development of multiple cancers, but its mechanism of action remains largely unstudied. To investigate the molecular function of SFTA1P in non-small cell lung cancer (NSCLC), Xia and colleagues evaluated SFTA1P for its impact on gene regulation and tumor progression. Proliferation, migration, and invasion assays using SFTA1P overexpressing and deficient lung cancer cells showed that SFTAP1 induced an inhibitory effect on cancer progression. In vivo subcutaneous xenograft tumor models and tail vein injection metastasis models using SFTA1P overexpressing lung cancer cells demonstrated a similar inhibitory effect on tumor development and dissemination compared to the control. The authors also analyzed the SFTA1P/miR-665/TGFBR2 regulatory network using luciferase reporter assays, RNA-seq data, and RNA immunoprecipitation assays, and found that the ceRNA SFTA1P may modulate TGFBR2 by sponging miR-665 in the cytoplasm. Additional GO analysis, GSEA, and RNA pull-down assays using SFTA1P overexpressing cells revealed that SFTA1P/P-TEFb complex interaction inhibited RNA Pol II function in the nucleus. RNA immunoprecipitation assays also found an interaction between nuclear m6A reader YTHDC1 and SFTA1P and showed a YTHDC1-dependent differential localization of SFTA1P. Taken together, this study demonstrates that SFTA1P functions as a tumor suppressor pseudogene in NSCLC by orchestrating TGFBR2 and P-TEFb interactions, revealing its clinical potential.N6-methyladenosine (m6A) modifications are widely acknowledged as significant players in cancer development and progression. Despite this, the function and mechanism of m6A in gastric cancer is poorly understood. In their study, Hu and colleagues evaluated m6A modifications in the context of gastric cancer by analyzing METTL3, a key enzyme involved in m6A deposition. Analysis of METTL3 knockdown cells using MTT, colony formation, and migration assays demonstrated a decrease in the proliferative ability of METTL3 deficient cells compared to the control. A Dot blot also showed a significant decrease in the RNA m6A level in METTL3 deficient cells. Interaction between METTL3 and FNTA, resulting in METTL3-mediated m6A deposition on FNTA, was observed using RNA immunoprecipitation assays. Further analysis of this interaction through RNA immunoprecipitation and computational tools demonstrated interaction between m6A reader YTHDF1 and FNTA mRNA, highlighting YTHDF1 as a regulator of FNTA translation. Luciferase assays validated the METTL3/YTHDF1/FNTA axis, and in vivo tumor models and tail vein metastasis models demonstrated the pro-tumoral function of METTL3 and FNTA. METTL3 was also shown to promote KRAS localization to the plasma membrane, resulting in enhanced MEK/ERK signaling. Altogether, this study shows that METTL3 is responsible for m6A modification deposition on FNTA in a YTHDF1-dependent manner, resulting in KRAS plasma membrane localization and cancer progression.