Cancer Cell International最新文献

Background: Malignant peripheral nerve sheath tumors (MPNSTs) represent the most severe complication of neurofibromatosis type 1 (NF1), with limited therapeutic options and poor prognosis. High-mobility group box 1 (HMGB1) is a chromatin-associated protein implicated in various cancers, yet its functional role and mechanistic involvement in NF1-MPNST progression remain poorly understood.

Methods: We integrated single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq analyses of patient-derived NF1-MPNST and plexiform neurofibroma (PNF) tissues. Functional validation was performed using NF1 cell lines with HMGB1 knockdown and overexpression. Mechanistic insights were explored via CUT&Tag, ChIP‒qPCR, qPCR, and Western blot. In vivo tumor growth was assessed using a xenograft mouse model.

Results: HMGB1 was significantly upregulated in malignant CNV-high subpopulations of MPNSTs and correlated with poor patient survival. Functional assays demonstrated that HMGB1 knockdown suppressed tumor proliferation, migration, and invasion, and induced G1 arrest, while its overexpression promoted these phenotypes. Mechanistically, HMGB1 directly bound to the E2F2 promoter and activated its transcription, thereby driving the G1/S transition. In vivo, HMGB1 overexpression accelerated tumor growth, whereas knockdown suppressed it, consistent with modulated E2F2 and Ki-67 expression.

Conclusions: Our study identifies HMGB1 as a key oncogenic driver in NF1-MPNST progression, functioning through direct transcriptional activation of E2F2 to promote cell cycle progression and tumor malignancy. These findings position HMGB1 as both a prognostic biomarker and a promising therapeutic target for NF1-associated MPNSTs.

The NF-κB interacting LncRNA (NKILA) is a recently identified long noncoding RNA (lncRNA) located on chromosome 20q13.31. Studies have indicated that abnormal levels of NKILA expression in different types of cancer can function as either oncogenes or tumour suppressors and play a role in the development of diverse malignancies. Moreover, NKILA expression levels correlate closely with the clinical features and prognosis of cancer patients, underscoring its potential significance in clinical practice. Multiple studies have shown that NKILA acts as a competing endogenous RNA (ceRNA), participating in several crucial signalling pathways and interacting with proteins to regulate gene expression. Furthermore, NKILA affects essential aspects of cancer cell behaviour, such as proliferation, migration, invasion, apoptosis, the epithelial-mesenchymal transition (EMT), and resistance to treatment. NKILA downregulation is associated with increased tumour size, advanced pathological stage, increased lymph node metastasis, and poor patient prognosis. This article reviews the expression patterns, clinical relevance, molecular mechanisms, and biological functions of NKILA, investigates its potential clinical roles as a therapeutic target and diagnostic marker, and evaluates its efficacy in treating various tumours.

Background: Anoikis is a critical mechanism that suppresses tumor metastasis. However, cancer cells evade anoikis by activating protective autophagy, thereby promoting metastasis. Although SPIB acts as a tumor suppressor in multiple cancers, its role in regulating autophagy-mediated anoikis resistance in colorectal cancer (CRC) remains unclear. This study aimed to investigate the impact of SPIB on anoikis resistance in CRC cells.

Methods: Bioinformatics analysis was employed to screen key genes regulating anoikis resistance in CRC. Stable SPIB knockdown/overexpression cell lines were constructed, and in vitro/in vivo experiments were conducted to examine SPIB's biological functions in CRC. Mechanistic insights were obtained via CCK-8, EdU, Transwell, CUT&Tag-seq, RNA-seq, dual-luciferase reporter assays, and mitochondrial membrane potential assays.

Results: SPIB expression was significantly reduced in CRC tissues and cell lines. Functionally, SPIB inhibited CRC progression both in vitro and in vivo. Mechanistically, SPIB transcriptionally activated IFIT2, which subsequently restored mitochondrial membrane potential(ΔΨm), thereby inhibiting protective autophagy through the PINK1/Parkin pathway and sensitizing CRC cells to anoikis.

Conclusion: Our results demonstrate that SPIB exerts tumor-suppressive effects during CRC invasion and metastasis through the IFIT2/PINK1/Parkin axis. This study highlights SPIB as a potential therapeutic target for overcoming anoikis resistance in CRC therapy.

Background: Neutrophils, serving as crucial innate immune cells, exert anti-tumor effects through cytotoxic mediators, antibody-dependent responses, and coordination of immune networks. They also release exosomes that carry bioactive molecules such as microRNAs (miRNAs). Our previous work identified neutrophil-derived exosomes (N-Exo) as contributors to their anti-tumor activity, but the underlying mechanisms remain unclear.

Methods: Functional experiments integrating high-throughput sequencing and validation assays were performed to screen and identify key anti-tumor miRNAs in N-Exo. An in vivo subcutaneous xenograft mouse tumor model assessed the therapeutic effects of N-Exo-delivered miR-101-3p on tumor growth. Bioinformatics analysis combined with experimental validation, including dual-luciferase reporter assays, co-immunoprecipitation (Co-IP), and chromatin immunoprecipitation (ChIP), elucidated the mechanism by which the key miRNA suppresses tumorigenesis through targeting specific genes and signaling pathways. Recombinant interleukin-36 gamma (rmIL-36γ) was used to stimulate neutrophils, and functional assays were performed to evaluate its effect.

Results: Hsa-miR-101-3p was enriched in N-Exo. N-Exo-delivered miR-101-3p directly targets MCL1 to suppress its expression and indirectly inhibits MCL1 transcription via regulation of the EZH2/c-Myc axis, collectively promoting apoptosis in gastric cancer (GC) cells. Furthermore, rmIL-36γ priming upregulated miR-101-3p expression in neutrophils and enhanced their anti-tumor effects.

Conclusion: We demonstrate that N-Exo exerts tumor-suppressive effects by delivering miR-101-3p, which dually targets and suppresses MCL1 expression. Moreover, rmIL-36γ treatment enhances both miR-101-3p abundance and anti-tumor efficacy in neutrophils. These findings highlight the N-Exo/miR-101-3p/MCL1 axis as a therapeutic target and support cytokine priming as a strategy to enhance neutrophil-based cancer therapy.