Molecular Cancer Research最新文献

Extravasation is a key step in tumor metastasis. Epstein‒Barr virus (EBV) plays a crucial role in nasopharyngeal carcinoma (NPC) metastasis. However, the functions and molecular mechanisms of EBV during tumor cell extravasation remains unclear. Here, we showed that the expression of pyroptosis-associated proteins is greater in the endothelial cells of metastatic NPC tissues than in those of nontumor tissues Exosomes derived from NPC cells promoted endothelial cell pyroptosis, vascular permeability, and tumor cell extravasation. Moreover, we found that BART2-5p is abundant in serum exosomes from NPC patients with metastasis and NPC cells, and that it regulates endothelial cell pyroptosis in pre-metastatic organs via MRE11A. Exosomes containing a BART2-5p inhibitor and AAV-MRE11A attenuated endothelial cell pyroptosis and tumor metastasis. Moreover, in the endothelial cells of metastatic tissues from NPC patients, the BART2-5p level was positively associated with pyroptosis-related protein expression. Collectively, our findings suggest that exosomal BART2-5p is involved in pre-metastatic niche formation, identifying secreted BART2-5p as a potential therapeutic target for NPC metastasis. Implications: The finding that secreted BART2-5p is involved in pre-metastatic niche formation may aid the development of potential therapeutic target for NPC metastasis.

TIPE is a protein highly expressed in various cancers that promotes ferroptosis in colorectal cancer (CRC) cells. Ferroptosis is a non-apoptotic cell death caused by lipid peroxidation, and MGST1 is a critical enzyme that resists lipid peroxidation. This study explored how TIPE regulates MGST1 expression to inhibit ferroptosis and promote CRC proliferation. TIPE was highly expressed in CRC tissues and positively correlated with the proliferation of human CRC cells. We measured levels of reactive oxygen species (ROS) and lipid-ROS in CRC cells with differential expression of TIPE and detected ferroptosis using transmission electron microscopy. Bioinformatics analysis revealed a positive correlation of expression patterns between TIPE and MGST1 in CRC. TIPE regulated the expression of MGST1 by activating the phosphorylation of ERK1/2. Co-immunoprecipitation revealed binding between MGST1 and ALOX5. This binding inhibited the phosphorylation of ALOX5, inhibiting ferroptosis and promoting the proliferation of CRC cells. A tumor formation experiment in nude mice supported our findings that TIPE regulates the proliferation of CRC by regulating ferroptosis. Implications: TIPE inhibits CRC ferroptosis via an MGST1-ALOX5 interaction to promote CRC proliferation. These findings suggest future CRC treatment strategies.

Despite aggressive, multimodal therapies, the prognosis of patients with refractory or recurrent rhabdomyosarcoma (RMS) has not improved in four decades. Because RMS resembles skeletal muscle precursor cells, differentiation-inducing therapy has been proposed for patients with advanced disease. In RAS-mutant PAX fusion-negative RMS (FN-FMS) preclinical models, MEK1/2 inhibition (MEKi) induces differentiation, slows tumor growth, and extends survival. However, the response is short-lived. A better understanding of the molecular mechanisms regulating FN-RMS differentiation could improve differentiation therapy. Here, we identified a role in FN-RMS differentiation for ASAP1, an ARF GTPase-activating protein (ARF GAP) with both pro-invasive and tumor suppressor functions. We found that ASAP1 knockdown inhibited differentiation in FN-RMS cells. Interestingly, knockdown of the GTPases ARF1 or ARF5, targets of ASAP1 GAP activity, also blocked differentiation of FN-RMS. We discovered that loss of ARF pathway components blocked myogenic transcription factor expression. Therefore, we examined the effects on transcriptional regulators. MEKi led to the phosphorylation and inactivation of WWTR1 (TAZ), a homolog of the pro-proliferative transcriptional co-activator YAP1 regulated by the Hippo pathway. However, loss of ASAP1 or ARF1 blocked this inactivation, which inhibits MEKi-induced differentiation. Finally, MEKi-induced differentiation was rescued by dual knockdown of ASAP1 and WWTR1. This study shows that ASAP1 and ARF1 are necessary for myogenic differentiation, providing a deeper understanding of differentiation in FN-RMS and illuminating an opportunity to advance differentiation therapy. Implications: ASAP1 and ARF1 regulate MEKi-induced differentiation of FN-RMS cells by modulating WWTR1 (TAZ) activity, supporting YAP1/TAZ inhibition as a FN-RMS differentiation therapy strategy.

Frequent (>70%) TP53 mutations often promote its protein stabilization, driving esophageal adenocarcinoma (EAC) development linked to poor survival and therapy resistance. We previously reported that during Barrett's esophagus progression to EAC, an isoform switch occurs in the E3 ubiquitin ligase RNF128 (aka GRAIL-gene related to anergy in lymphocytes), enriching isoform 1 (hereby GRAIL1) and stabilizing the mutant p53 protein. Consequently, GRAIL1 knockdown degrades mutant p53. But, how GRAIL1 stabilizes the mutant p53 protein remains unclear. In search for a mechanism, here, we performed biochemical and cell biology studies to identify that GRAIL has a binding domain (315-PMCKCDILKA-325) for heat shock protein 40/DNAJ. This interaction can influence DNAJ chaperone activity to modulate misfolded mutant p53 stability. As predicted, either the overexpression of a GRAIL fragment (Frag-J) encompassing the DNAJ binding domain or a cell-permeable peptide (Pep-J) encoding the above 10 amino acids can bind and inhibit DNAJ-Hsp70 co-chaperone activity, thus degrading misfolded mutant p53. Consequently, either Frag-J or Pep-J can reduce the survival of mutant p53 containing dysplastic Barrett's esophagus and EAC cells and inhibit the growth of patient-derived organoids of dysplastic Barrett's esophagus in 3D cultures. The misfolded mutant p53 targeting and growth inhibitory effects of Pep-J are comparable with simvastatin, a cholesterol-lowering drug that can degrade misfolded mutant p53 also via inhibiting DNAJA1, although by a distinct mechanism. Implications: We identified a novel ubiquitin ligase-independent, chaperone-regulating domain in GRAIL and further synthesized a first-in-class novel misfolded mutant p53 degrading peptide having future translational potential.

Colorectal cancer (CRC) tumors start as polyps on the inner lining of the colorectum, where they are exposed to the mechanics of peristalsis. Our previous work leveraged a custom-built peristalsis bioreactor to demonstrate that colonic peristalsis led to cancer stem cell enrichment in CRC cells. However, this malignant mechanotransductive response was confined to select CRC lines that harbored an oncogenic mutation in the KRAS gene. Here, we explored the involvement of activating KRAS mutations on peristalsis-associated mechanotransduction in CRC. Peristalsis enriched cancer stem cell marker LGR5 in KRAS mutant lines, in a Wnt-ligand-independent manner. Conversely, LGR5 enrichment in wild type KRAS lines exposed to peristalsis were minimal. LGR5 enrichment downstream of peristalsis translated to increased tumorigenicity in vivo. Differences in mechanotransduction was apparent via unbiased gene set enrichment analysis, where many unique pathways were enriched in wild type vs. mutant lines. Peristalsis also triggered β-catenin nuclear localization independent of Wnt-ligands, particularly in KRAS mutant lines. The involvement of KRAS was validated via gain and loss of function strategies. Peristalsis induced β-catenin activation and LGR5 enrichment depended on the activation of the MEK/ERK cascade. Taken together, our results demonstrated that oncogenic KRAS mutations conferred a unique peristalsis-associated mechanotransduction response to colorectal cancer cells, resulting in cancer stem cell enrichment and increased tumorigenicity. These mechanosensory connections can be leveraged in improving the sensitivity of emerging therapies that target oncogenic KRAS. Implications: Oncogenic KRAS empowers colorectal cancer cells to harness the mechanics of colonic peristalsis for malignant gain, independent of other cooperating signals. .