Hepatocellular carcinoma (HCC) prognosis remains dismal due to postsurgical recurrence and distant metastasis. Therefore, novel prognostic biomarkers and therapeutic targets for HCC therapy are urgently needed to improve the survival of liver cancer patients. Our evidence suggests that SLC46A3 (the gene solute carrier family 46 (sodium phosphate), member 3) is a member of the SLC46 family and has a potential role in the progression and treatment of HCC. The objective of the present study was to estimate the expression pattern and biological function of SLC46A3 in the progression of HCC, which may serve as a promising biomarker for diagnosis and therapy. In order to determine the expression pattern of SLC46A3 in HCC, several public HCC databases and tissue chips were used to examine 129 sets of primary HCC and non-tumor adjacent tissues from patients who had undergone surgery. The expression of SLC46A3 in 80 sets of HCC and non-tumor adjacent tissues were then compared by RT-PCR and Western Blot. The proliferation, invasion, migration and sphere-forming abilities of SLC46A3 knock-down and overexpressing cell lines were evaluated and the expression of related molecules in the epithelial mesenchymal transition (EMT) were detected by RT-PCR, western blot and immunofluorescence assay. The IC₅₀ value was used to evaluate the effect of SLC46A3 on sorafenib resistance. A lung metastasis model of mice HCC was constructed to test the potential effect of SLC46A3 on cancer metastasis and a subcutaneous xenografted tumor mice model was designed to verify the effect of SLC46A3 on the resistance of HCC cell lines to sorafenib. The expression of SLC46A3 was down-regulated in 83.2% of human HCC tissues compared to non-tumor adjacent tissues. Tumors that expressed low levels of SLC46A3 had more aggressive phenotypes, and patients with these tumors had shorter survival times after surgery compared to patients whose tumors expressed high levels of SLC46A3. Hepatocellular carcinoma cell lines that stably overexpressed SLC46A3 inhibited the levels of migration and invasion compared with control HCC cells, and formed smaller xenograft tumors with more metastases in mice compared with HCC cells that did not overexpress SLC46A3. In addition, overexpression of SLC46A3 obviously inhibited epithelial-to-mesenchymal transition-activating transcription factors such as N-cadherin and Vimentin. Furthermore, descended of IC₅₀ showed that overexpressed SLC46A3 could reduce sorafenib resistance and improve drug response in vivo and in vitro. In conclusion, increased expression of SLC46A3 could favor a better clinical prognosis for patients with HCC, ameliorate sorafenib resistance, and improve drug response. SLC46A3 might serve as a potential prognostic biomarker and therapeutic target in HCC.

Multiple myeloma(MM) remains incurable with high relapse and chemoresistance rates. Differentially expressed genes(DEGs) between newly diagnosed myeloma and secondary plasma cell leukemia(sPCL) were subjected to a weighted gene co-expression network analysis(WGCNA). Drug resistant myeloma cell lines were established. Seahorse XF analyzer was applied to detect the metabolism reprogramming associated with the hub gene. The metabolic relevance and the underlying mechanism of the hub gene in myeloma resistance were explored via in vitro experiments. A total of 1310 DEGs were used to construct five co-expression modules. Gene function enrichment analysis demonstrated that candidate hub genes were closely related to oxidative phosphorylation. We performed prognostic analysis and identified PSMA4 as the key hub gene related to the extramedullary invasion of myeloma. The in vitro experiments demonstrated bortezomib resistant myeloma cell lines exhibited high PSMA4 expression, improved oxidative phosphorylation activity with increased ROS level. PSMA4 knockdown re-sensitize resistant myeloma cells via suppressing oxidative phosphorylation activity. Further investigation revealed that PSMA4 induced a hypoxia state which activated the HIF-1α signaling pathway. PSMA4 induces metabolic reprogramming by improving oxidative phosphorylation activity which accounts for the hypoxia state in myeloma cell. The activated HIF-1α signaling pathway causes bortezomib resistance via promoting anti-apoptotic activity in myeloma.

Extramedullary blast crisis (EMBC) is rare, clinically heterogeneous, and often misdiagnosed because routine histology may be inconclusive. We describe a CML-EMBC case in which targeted RNA sequencing uncovered concurrent NPM1::CCDC28A and BCR::ABL1 fusions, refining the diagnosis and suggesting a novel molecular subset.Clinical, laboratory, imaging, histopathology, and outcome data of a 26-year-old man were reviewed retrospectively. Targeted RNA-seq was performed on formalin-fixed, paraffin-embedded sacrococcygeal tissue. PubMed and Google Scholar were searched with “NPM1,” “CCDC28A,” “fusion,” “CML,” “myeloid sarcoma,” and “extramedullary blast crisis” to contextualise NPM1 rearrangements. The patient achieved deep molecular remission of chronic-phase CML (BCR::ABL1 0.0058% International Scale) while receiving flumatinib, yet developed a painful sacrococcygeal mass. Initial biopsy suggested an undifferentiated small round-cell sarcoma. RNA-seq revealed dual NPM1::CCDC28A and BCR::ABL1 fusions, prompting reclassification as granulocytic sarcoma-type CML-EMBC. Intermediate-dose cytarabine with continued tyrosine-kinase inhibition produced marked metabolic regression on PET-CT, and the patient has been bridged to allogeneic hematopoietic stem-cell transplantation. Literature review uncovered only sporadic reports of NPM1::CCDC28A; experimental data indicate that the fusion up-regulates HOX clusters similarly to mutant NPM1, facilitating leukemogenesis and extramedullary dissemination. Solitary tumours in CML patients who are in marrow remission should prompt suspicion for EMBC. When morphology is ambiguous, integrating molecular pathology, particularly targeted RNA-seq, can confirm myeloid lineage and uncover disease-relevant alterations. Co-occurrence of BCR::ABL1 and NPM1::CCDC28A may delineate a distinct EMBC subset with prognostic and therapeutic relevance. Prospective studies are required to clarify the fusion’s pathogenic role and biomarker potential.

Circular RNA (circRNA) possesses great pre-clinical diagnostic and therapeutic potentials in multiple cancers. However, the underlying correlation between circRNAs and cancer stem cells (CSCs) has not been reported. The absence of circZKSCAN1 endowed several malignant properties including cancer stemness and tightly correlated with worse overall and recurrence-free survival rate in HCC cells in vitro and in vivo. Bioinformatics analysis and RNA immunoprecipitation-sequencing (RIP-seq) results revealed that circZKSCAN1 exerted its inhibitive role by competitively binding FMRP, therefore, block the binding between FMRP and β-catenin-binding protein-cell cycle and apoptosis regulator 1 (CCAR1) mRNA, and subsequently restraining the transcriptional activity of Wnt signaling. In addition, RNA-splicing protein Quaking 5 was found downregulated in HCC tissues and responsible for the reduction of circZKSCAN1. Collectively, this study revealed the mechanisms underlying the regulatory role of circZKSCAN1 in HCC CSCs and identified the newly discovered Qki5-circZKSCAN1-FMRP-CCAR1-Wnt signaling axis as a potentially important therapeutic target for HCC treatment.