BACKGROUND: Zinc finger SWIM-type containing 4 (ZSWIM4) is a zinc finger protein with its function largely uncharacterized. In this study, we aimed to investigate the role of ZSWIM4 in gastrointestinal stromal tumors (GISTs).
RESULTS: We found that ZSWIM4 expression is inhibited by the predominantly mutated protein KIT in GISTs, while conversely, ZSWIM4 inhibits KIT expression and downstream signaling. Consistent with the observation, ZSWIM4 inhibited GIST cell survival and proliferation in vitro. RNA sequencing of GISTs from KITV558A/WT mice and KITV558A/WT/ZSWIM4-/- mice showed that loss of ZSWIM4 expression increases the expression of circadian clock pathway member BMAL1 which contributes to GIST cell survival and proliferation. In addition, we found that KIT signaling increases the distribution of ZSWIM4 in the nucleus of GIST cells, and which is important for its inhibition of KIT and BMAL1. In agreement with the results in vitro, the in vivo studies showed that ZSWIM4 deficiency increases the tumorigenesis of GISTs in KITV558A/WT mice.
CONCLUSIONS: Taken together, our results revealed that the entry of ZSWIM4 to the nucleus is important for its inhibition of KIT and BMAL1, ultimately attenuating GIST tumorigenesis. The results provide a novel insight in the understanding of signal transduction in GISTs and lay strong theoretical basis for the advancement of GIST treatment.

The receptor tyrosine kinase (RTK) KIT and its ligand stem cell factor (SCF) are essential for human mast cell (huMC) survival and proliferation. HuMCs expressing oncogenic KIT variants secrete large numbers of extracellular vesicles (EVs). The role KIT plays in regulating EV secretion has not been examined. Here, we investigated the effects of stimulation or inhibition of KIT activity on the secretion of small EVs (sEVs). In huMCs expressing constitutively active KIT, the quantity and quality of secreted sEVs positively correlated with the activity status of KIT. SCF-mediated stimulation of KIT in huMCs or murine MCs, or of transiently expressed KIT in HeLa cells, enhanced the release of sEVs expressing exosome markers. In contrast, ligand-mediated stimulation of the RTK EGFR in HeLa cells did not affect sEV secretion. The release of sEVs induced by either constitutively active or ligand-activated KIT was remarkably decreased when cells were treated with KIT inhibitors, concomitant with reduced exosome markers in sEVs. Similarly, inhibition of oncogenic KIT signalling kinases like PI3K, and MAPK significantly reduced the secretion of sEVs. Thus, activation of KIT and its early signalling cascades stimulate the secretion of exosome-like sEVs in a regulated fashion, which may have implications for KIT-driven functions.

Kaposi sarcoma (KS) is a low-grade vascular neoplasm that can be seen in various sites, most commonly seen in skin and mucosal tissues. Cytologic features of KS have been well-documented in the literature, however, since it is rarely seen in visceral organs, it could pose significant diagnostic challenges on fine needle aspiration (FNA) biopsies. We present a case of pulmonary KS diagnosed on transbronchial FNA biopsy in a 70-year-old female bilateral lung allograft recipient 11 months after transplantation. The aspirate smears showed a moderately cellular specimen containing a mixture of small, tightly cohesive clusters and loosely clustered groups of monomorphic, ovoid to spindled cells with moderate nuclear to cytoplasmic ratio. An extensive immunohistochemical panel on the concurrent core biopsy showed the tumor cells to be positive for ERG, KIT, and HHV8, confirming the diagnosis. We compared our case to previously published reports of confirmed pulmonary KS in lung allograft recipients.

暂无摘要。

Gastrointestinal stromal tumors (GISTs) are neoplasms arising from the bowel wall, most often in the jejunoileum of the small intestine, but rarely from extragastrointestinal locations. GISTs most often occur in patients older than 40 years of age and can present with a multitude of gastrointestinal symptoms. We present a rare case of an extragastrointestinal stromal tumor (EGIST) causing abdominal pain and melena in a 34-year-old Hispanic male. The patient presented with diffuse abdominal pain, melena, and severe anemia. Computed tomography of the abdomen revealed a large mass abutting the small bowel. The patient was taken to surgery where the mass, which appeared to be deriving from the omentum and invading the adjacent small bowel, was completely excised and found to be a spindle cell GIST. Excision margins were determined to be negative, and the patient was started on a tyrosine kinase inhibitor for maintenance therapy. The patient continues to follow up on an outpatient basis for surveillance. This case represents the rare disease entity EGIST presenting outside the typical demographics of the disease in a young patient with no identified previous genetic syndromes. Gross examination of the mass in this case was also atypical given the appearance that the mass was rooted in the omentum and invading the small bowel which would suggest the primary tumor site was extragastrointestinal. This case demonstrates the need to build a differential diagnosis that includes GIST and the ability to successfully treat this disease if it is identified early in the clinical course.

UNASSIGNED: Indonesian civilization extensively uses traditional medicine to cure illnesses and preserve health. The lack of knowledge on the security and efficacy of medicinal plants is still a significant concern. Although the precise chemicals responsible for this impact are unknown, ginger is a common medicinal plant in Southeast Asia that may have anticancer qualities.
UNASSIGNED: Using data from Dudedocking, a machine-learning model was created to predict possible breast anticancer chemicals from ginger. The model was used to forecast substances that block KIT and MAPK2 proteins, essential elements in breast cancer.
UNASSIGNED: Beta-carotene, 5-Hydroxy-74\'-dimethoxyflavone, [12]-Shogaol, Isogingerenone B, curcumin, Trans-[10]-Shogaol, Gingerenone A, Dihydrocurcumin, and demethoxycurcumin were all superior to the reference ligand for MAPK2, according to molecular docking studies. Lycopene, [8]-Shogaol, [6]-Shogaol, and [1]-Paradol exhibited low toxicity and no Lipinski violations, but beta carotene had toxic predictions and Lipinski violations. It was anticipated that all three substances would have anticarcinogenic qualities.
UNASSIGNED: Overall, this study shows the value of machine learning in drug development and offers insightful information on possible anticancer chemicals from ginger.

KIT ligand and its associated receptor KIT serve as a master regulatory system for both melanocytes and mast cells controlling survival, migration, proliferation and activation. Blockade of this pathway results in cell depletion, while overactivation leads to mastocytosis or melanoma. Expression defects are associated with pigmentary and mast cell disorders. KIT ligand regulation is complex but efficient targeting of this system would be of significant benefit to those suffering from melanocytic or mast cell disorders. Herein, we review the known associations of this pathway with cutaneous diseases and the regulators of this system both in skin and in the more well-studied germ cell system. Exogenous agents modulating this pathway will also be presented. Ultimately, we will review potential therapeutic opportunities to help our patients with melanocytic and mast cell disease processes potentially including vitiligo, hair greying, melasma, urticaria, mastocytosis and melanoma.

The high-affinity IgE receptor FcεRI is the mast cell (MC) receptor responsible for the involvement of MCs in IgE-associated allergic disorders. Activation of the FcεRI is achieved via crosslinking by multivalent antigen (Ag) recognized by IgE resulting in degranulation and proinflammatory cytokine production. In comparison to the T- and B-cell receptor complexes, for which several co-receptors orchestrating the initial signaling events have been described, information is scarce about FcεRI-associated proteins. Additionally, it is unclear how FcεRI signaling synergizes with input from other receptors and how regulators affect this synergistic response. We found that the HDL receptor SR-BI (gene name: Scarb1/SCARB1) is expressed in MCs, functionally associates with FcεRI, and regulates the plasma membrane cholesterol content in cholesterol-rich plasma membrane nanodomains. This impacted the activation of MCs upon co-stimulation of the FcεRI with receptors known to synergize with FcεRI signaling. Amongst them, we investigated the co-activation of the FcεRI with the receptor tyrosine kinase KIT, the IL-33 receptor, and GPCRs activated by adenosine or PGE2. Scarb1-deficient bone marrow-derived MCs showed reduced cytokine secretion upon co-stimulation conditions suggesting a role for plasma membrane-associated cholesterol regulating respective MC activation. Mimicking Scarb1 deficiency by cholesterol depletion employing MβCD, we identified PKB and PLCγ1 as cholesterol-sensitive proteins downstream of FcεRI activation in bone marrow-derived MCs. When MCs were co-stimulated with stem cell factor (SCF) and Ag, PLCγ1 activation was boosted, which could be mitigated by cholesterol depletion and SR-BI inhibition. Similarly, SR-BI inhibition attenuated the synergistic response to PGE2 and anti-IgE in the human ROSAKIT WT MC line, suggesting that SR-BI is a crucial regulator of synergistic MC activation.

Normal receptor tyrosine kinases (RTKs) need to reach the plasma membrane (PM) for ligand-induced activation, whereas its cancer-causing mutants can be activated before reaching the PM in organelles, such as the Golgi/trans-Golgi network (TGN). Inhibitors of protein export from the endoplasmic reticulum (ER), such as brefeldin A (BFA) and 2-methylcoprophilinamide (M-COPA), can suppress the activation of mutant RTKs in cancer cells, suggesting that RTK mutants cannot initiate signaling in the ER. BFA and M-COPA block the function of ADP-ribosylation factors (ARFs) that play a crucial role in ER-Golgi protein trafficking. However, among ARF family proteins, the specific ARFs inhibited by BFA or M-COPA, that is, the ARFs involved in RTKs transport from the ER, remain unclear. In this study, we showed that M-COPA blocked the export of not only KIT but also PDGFRA/EGFR/MET RTKs from the ER. ER-retained RTKs could not fully transduce anti-apoptotic signals, thereby leading to cancer cell apoptosis. Moreover, a single knockdown of ARF1, ARF3, ARF4, ARF5, or ARF6 could not block ER export of RTKs, indicating that BFA/M-COPA treatment cannot be mimicked by the knockdown of only one ARF member. Interestingly, simultaneous transfection of ARF1, ARF4, and ARF5 siRNAs mirrored the effect of BFA/M-COPA treatment. Consistent with these results, in vitro pulldown assays showed that BFA/M-COPA blocked the function of ARF1, ARF4, and ARF5. Taken together, these results suggest that BFA/M-COPA targets at least ARF1, ARF4, and ARF5; in other words, RTKs require the simultaneous activation of ARF1, ARF4, and ARF5 for their ER export.

Gastrointestinal stromal tumors (GISTs) are predominately induced by KIT mutants. In this study, we found that four and a half LIM domains 2 (FHL2) was highly expressed in GISTs and KIT signaling dramatically increased FHL2 transcription while FHL2 inhibited KIT transcription. In addition, our results showed that FHL2 associated with KIT and increased the ubiquitination of both wild-type KIT and primary KIT mutants in GISTs, leading to decreased expression and activation of KIT although primary KIT mutants were less inhibited by FHL2 than wild-type KIT. In the animal experiments, loss of FHL2 expression in mice carrying germline KIT/V558A mutation which can develop GISTs resulted in increased tumor growth, but increased sensitivity of GISTs to imatinib treatment which is used as the first-line targeted therapy of GISTs, suggesting that FHL2 plays a role in the response of GISTs to KIT inhibitor. Unlike wild-type KIT and primary KIT mutants, we further found that FHL2 didn\'t alter the expression and activation of drug-resistant secondary KIT mutants. Taken together, our results indicated that FHL2 acts as the negative feedback of KIT signaling in GISTs while primary KIT mutants are less sensitive and secondary KIT mutants are resistant to the inhibition of FHL2.