SHCBP1 Overexpression Aggravates Pancreatitis by Triggering the Loss of Primary Cilia.

Primary cilia are microtubule-based organelles that mediate various biological processes. Pancreatic cells are typically ciliated; however, the role of primary cilia in acute pancreatitis (AP) is largely unknown. Here, we report that the loss of primary cilia, mediated by SHCBP1 (SHC1 binding protein), exerted a provocative effect on AP. Primary cilia are extensively lost in inflamed pancreatic cells in vitro and in mouse tissues with AP in vivo. Abrogation of primary cilia aggravated lipopolysaccharide (LPS)-induced inflammation in pancreatic cells. Mechanistically, AP induced the overexpression of SHCBP1 mitotic factor, which is localized to the base of primary cilia. SHCBP1 deficiency relieved LPS- and cerulein-induced pancreatitis by preventing the loss of primary cilia in vitro and in vivo. Collectively, we reveal that inflammation-induced loss of primary cilia aggravates AP. Furthermore, abrogating SHCBP1 to prevent primary cilia loss is an efficient strategy to combat AP.

PICH Activates Cyclin A1 Transcription to Drive S-Phase Progression and Chemoresistance in Gastric Cancer.

The chemotherapeutic agent 5-fluorouracil (5-FU) remains the backbone of postoperative adjuvant treatment for gastric cancer. However, fewer than half of patients with gastric cancer benefit from 5-FU-based chemotherapies owing to chemoresistance and limited clinical biomarkers. Here, we identified the SNF2 protein Polo-like kinase 1-interacting checkpoint helicase (PICH) as a predictor of 5-FU chemosensitivity and characterized a transcriptional function of PICH distinct from its role in chromosome separation. PICH formed a transcriptional complex with RNA polymerase II (Pol II) and ATF4 at the CCNA1 promoter in an ATPase-dependent manner. Binding of the PICH complex promoted cyclin A1 transcription and accelerated S-phase progression. Overexpressed PICH impaired 5-FU chemosensitivity in human organoids and patient-derived xenografts. Furthermore, elevated PICH expression was negatively correlated with survival in postoperative patients receiving 5-FU chemotherapy. Together, these findings reveal an ATPase-dependent transcriptional function of PICH that promotes cyclin A1 transcription to drive 5-FU chemoresistance, providing a potential predictive biomarker of 5-FU chemosensitivity for postoperative patients with gastric cancer and prompting further investigation into the transcriptional activity of PICH. SIGNIFICANCE: PICH binds Pol II and ATF4 in an ATPase-dependent manner to form a transcriptional complex that promotes cyclin A1 expression, accelerates S-phase progression, and impairs 5-FU chemosensitivity in gastric cancer.

Targeting UBE2T Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Regulating Pyrimidine Metabolism and Replication Stress.

BACKGROUND & AIMS: Although small patient subsets benefit from current targeted strategies or immunotherapy, gemcitabine remains the first-line drug for pancreatic cancer (PC) treatment. However, gemcitabine resistance is widespread and compromises long-term survival. Here, we identified ubiquitin-conjugating enzyme E2T (UBE2T) as a potential therapeutic target to combat gemcitabine resistance in PC. METHODS: Proteomics and metabolomics were combined to examine the effect of UBE2T on pyrimidine metabolism remodeling. Spontaneous PC mice (LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre; KPC) with Ube2t-conditional knockout, organoids, and large-scale clinical samples were used to determine the effect of UBE2T on gemcitabine efficacy. Organoids, patient-derived xenografts (PDX), and KPC mice were used to examine the efficacy of the combination of a UBE2T inhibitor and gemcitabine. RESULTS: Spontaneous PC mice with Ube2t deletion had a marked survival advantage after gemcitabine treatment, and UBE2T levels were positively correlated with gemcitabine resistance in clinical patients. Mechanistically, UBE2T catalyzes ring finger protein 1 (RING1)-mediated ubiquitination of p53 and relieves the transcriptional repression of ribonucleotide reductase subunits M1 and M2, resulting in unrestrained pyrimidine biosynthesis and alleviation of replication stress. Additionally, high-throughput compound library screening using organoids identified pentagalloylglucose (PGG) as a potent UBE2T inhibitor and gemcitabine sensitizer. The combination of gemcitabine and PGG diminished tumor growth in PDX models and prolonged long-term survival in spontaneous PC mice. CONCLUSIONS: Collectively, UBE2T-mediated p53 degradation confers PC gemcitabine resistance by promoting pyrimidine biosynthesis and alleviating replication stress. This study offers an opportunity to improve PC survival by targeting UBE2T and develop a promising gemcitabine sensitizer in clinical translation setting.

Combined Inhibition of KIF11 and KIF15 as an Effective Therapeutic Strategy for Gastric Cancer.

BACKGROUND: Novel therapeutic strategies are urgently required to improve clinical outcomes of gastric cancer (GC). KIF15 cooperates with KIF11 to promote bipolar spindle assembly and formation, which is essential for proper sister chromatid segregation. Therefore, we speculated that the combined inhibition of KIF11 and KIF15 might be an effective strategy for GC treatment. Hence, to test this hypothesis, we aimed to evaluate the combined therapeutic effect of KIF15 inhibitor KIF15- IN-1 and KIF11 inhibitor ispinesib in GC. METHODS: We validated the expression of KIF11 and KIF15 in GC tissues using immunohistochemistry and immunoblotting. Next, we determined the effects of KIF11 or KIF15 knockout on the proliferation of GC cell lines. Finally, we investigated the combined effects of the KIF11 and KIF15 inhibitors both in vitro and in vivo. RESULTS: KIF11 and KIF15 were overexpressed in GC tissues than in the adjacent normal tissues. Knockout of either KIF11 or KIF15 inhibited the proliferative and clonogenic abilities of GC cells. We found that the KIF15 knockout significantly increased ispinesib sensitivity in GC cells, while its overexpression showed the opposite effect. Further, using KIF15-IN-1 and ispinesib together had a synergistic effect on the antitumor proliferation of GC both in vitro and in vivo. CONCLUSION: This study shows that the combination therapy of inhibiting KIF11 and KIF15 might be an effective therapeutic strategy against gastric cancer.

Gated Molecular Diffusion at Liquid-Liquid Interfaces.

The jamming of nanoparticle surfactants (NPSs) at liquid-liquid interface imparts attractive properties to the interfacial assemblies and enables the structuring of liquids. Herein, we report photoresponsive supramolecular microcapsules with jammed NPS assemblies at the oil-water interface, taking advantage of host-guest molecular recognition. The permeability of the colloidal membrane can be effectively manipulated by switching the NPSs from a jammed state to an unjammed state with a photo trigger, leading to a controlled molecular diffusion and release, affording a versatile platform for the construction of next generation smart microcapsule systems.

Hyperactivation of HER2-SHCBP1-PLK1 axis promotes tumor cell mitosis and impairs trastuzumab sensitivity to gastric cancer.

Trastuzumab is the backbone of HER2-directed gastric cancer therapy, but poor patient response due to insufficient cell sensitivity and drug resistance remains a clinical challenge. Here, we report that HER2 is involved in cell mitotic promotion for tumorigenesis by hyperactivating a crucial HER2-SHCBP1-PLK1 axis that drives trastuzumab sensitivity and is targeted therapeutically. SHCBP1 is an Shc1-binding protein but is detached from scaffold protein Shc1 following HER2 activation. Released SHCBP1 responds to HER2 cascade by translocating into the nucleus following Ser273 phosphorylation, and then contributing to cell mitosis regulation through binding with PLK1 to promote the phosphorylation of the mitotic interactor MISP. Meanwhile, Shc1 is recruited to HER2 for MAPK or PI3K pathways activation. Also, clinical evidence shows that increased SHCBP1 prognosticates a poor response of patients to trastuzumab therapy. Theaflavine-3, 3'-digallate (TFBG) is identified as an inhibitor of the SHCBP1-PLK1 interaction, which is a potential trastuzumab sensitizing agent and, in combination with trastuzumab, is highly efficacious in suppressing HER2-positive gastric cancer growth. These findings suggest an aberrant mitotic HER2-SHCBP1-PLK1 axis underlies trastuzumab sensitivity and offer a new strategy to combat gastric cancer.

Redox-Responsive, Reconfigurable All-Liquid Constructs.

Using host-guest chemistries in a biphasic system, a novel supramolecular nanoparticle surfactant (s-NPS) with redox-responsiveness is presented to structure liquids. The in situ assembly/jamming and disassembly/unjamming of s-NPSs at the oil-water interface are reversibly controlled by a switchable redox process, imparting a nanoscale redox-responsiveness, affecting the assemblies on all length scales. "Smart" all-liquid constructs including structured emulsions and programmable liquid devices are easily prepared, showing promising applications in responsive delivery, release, and reaction systems.

Photoresponsive Structured Liquids Enabled by Molecular Recognition at Liquid-Liquid Interfaces.

Using host-guest molecular recognition at the oil-water interface, a new type of photoresponsive nanoparticle surfactant (NPS) was designed and prepared to structure liquids. With the help of a polymeric surfactant, the interfacial host-guest interactions can be significantly enhanced, leading to the rapid formation and assembly of a NP monolayer and offering sufficient binding energy to hold the NPs in a jammed state. The assembly of the NPSs can be reversibly manipulated via a photoswitchable jamming-to-unjamming transition, endowing the interface as well as the macroscopic assemblies with responsiveness to the external trigger (photons). This study for the first time opens a pathway for the construction of multiresponsive, structured all-liquid systems by introducing host-guest chemistry, showing promising potential applications in encapsulation, delivery systems, and unique microfluidic devices.

[Research progress of Lauren classification for gastric cancer].

Gastric cancer (GC) is one of the most common malignant tumors with high heterogeneity. According to Lauren classification, GC is divided into intestinal type and diffuse type. With rapid progress in technologies and ideas in the clinical diagnosis for GC, the normalized and individualized comprehensive treatment has become the main trend. However, the clinicopathological characteristics, remedy and prognosis for GC may be different because of the different classifications and stages.