LHPP promotes the intracellular reactive oxygen species accumulation and sensitivity of gastric cancer to cisplatin via JNK and p38 MAPK pathways.

BACKGROUND: Cisplatin is the first-line chemotherapy drug for the treatment of gastric cancer (GC) patients. However, GC patients who are resistant to cisplatin often do not benefit from it. Therefore, finding a key molecule that affects cisplatin sensitivity is expected to enhance the efficacy of cisplatin in GC treatment. METHODS: The human GC cell lines SGC-7901 and BGC-823 were used. The protein chip array was used to screen the cisplatin-resistance genes from the complete response and non-complete response GC patients' tissues, then, the differential gene expression analysis, GO function annotation analysis, and KEGG pathway enrichment analysis were performed. The GC tissue chip in the GEO database was analyzed to screen the target gene. Flow cytometry, Hoechst 33342 staining assay, Western Blot, MTT, tumor sphere formation, cell cycle, and apoptosis assays were performed to explore the effect of Phospholysine Phosphohistidine Inorganic Pyrophosphate Phosphatase (LHPP) on the apoptosis, stemness, and reactive oxygen species (ROS) accumulation of cisplatin-resistant GC cells treated with cisplatin. In vivo, the cisplatin-resistant GC cell lines transfected with pcDNA-LHPP or si-LHPP were injected subcutaneously into mice to construct GC subcutaneous xenograft GC models. RESULTS: Based on protein chip array and bioinformatics analysis, it was found that LHPP is the core molecule in the cisplatin resistance regulatory network in GC, and its expression is down-regulated in GC cisplatin-resistant tissues and cells. In vitro and in vivo experimental results show that the up-regulated expression of LHPP is closely related to the increase in sensitivity of GC to cisplatin. Mechanically, we found that overexpression of LHPP may inhibit the activation of the JNK and p38 MAPK pathways, promote cisplatin-induced ROS accumulation, suppress stemness, and enhance the sensitivity of GC to cisplatin. CONCLUSIONS: Up-regulation of LHPP may inhibit the activation of the JNK and p38 MAPK pathways, attenuate stemness, and enhance the accumulation of intracellular ROS, thereby promoting cisplatin-mediated GC cell apoptosis and enhancing cisplatin sensitivity.

Self-healing, injectable hydrogel based on dual dynamic covalent cross-linking against postoperative abdominal cavity adhesion.

Clinically, increasing the peritoneal barrier is an effective adjunct to reducing postoperative peritoneal adhesion. This study presents a facile template for preparing a supramolecular hybrid hydrogel through dynamic covalent cross-linking between carboxymethyl chitosan (CMCS), 2-formylphenylboronic acid (2-FPBA), and quercetin (Que). The as-prepared complex CMCS/2-FPBA/Que (CFQ) hydrogel exhibited favorable antibacterial, anti-inflammatory, and antioxidant effects. A L929 cytotoxicity evaluation confirmed the favorable cytocompatibility of the CFQ hydrogel. The postoperative anti-adhesion ability of the CFQ hydrogel was further evaluated in rats with lateral wall defects and cecal abrasions. Compared with control groups, the tissue adhesion rate was significantly reduced by increasing the Que concentration in all the hydrogel-treated groups. Additionally, the sustained-release time of the C3F0.8Q0.08 hydrogel can exceed 14 days, which is highly desirable for clinical wound treatment. STATEMENT OF SIGNIFICANCE: Postoperative adhesions are a very common postoperative complication that seriously affects the quality of life of patients. The currently commonly used methods for preventing adhesion mainly use degradable barrier materials for physical separation. In this study, we prepared a dual dynamic covalently cross-linked CFQ hydrogel, which is not only degradable and injectable, but also has multiple properties such as antibacterial, antioxidant and anti-inflammatory, which can effectively prevent postoperative adhesion and promote wound healing.

Metallothionein 2A (MT2A) controls cell proliferation and liver metastasis by controlling the MST1/LATS2/YAP1 signaling pathway in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the three major cancers in the world and is the cancer with the most liver metastasis. The present study aimed to investigate the role of metallothionein 2A (MT2A) in the modulation of CRC cell proliferation and liver metastasis, as well as its molecular mechanisms. METHODS: The expression profile of metallothionein 2A (MT2A) in colorectal cancer retrieved from TCGA, GEO and Oncomine database. The biological effect of MT2A overexpression was investigated mainly involving cell proliferation and migration in CRC cells as well as growth and metastasis in CRC animal models. To explore the specific mechanism of MT2A metastasis in CRC, transcriptome sequencing was used to compare the overall expression difference between the control group and the MT2A overexpression group. RESULTS: Metallothionein 2A (MT2A) was downregulated in the tumor tissues of patients with CRC compared to adjacent normal tissues and was related to the tumor M stage of patients. MT2A overexpression inhibited CRC cell proliferation and migration in cells, as well as growth and metastasis in CRC animal models. While knockdown of MT2A had the opposite effect in cells. Western blotting confirmed that MT2A overexpression promoted the phosphorylation of MST1, LAST2 and YAP1, thereby inhibiting the Hippo signaling pathway. Additionally, specific inhibitors of MST1/2 inhibited MT2A overexpression-mediated phosphorylation and relieved the inhibition of the Hippo signaling pathway, thus promoting cell proliferation. Immunohistochemistry in subcutaneous grafts and liver metastases further confirmed this result. CONCLUSIONS: Our results suggested that MT2A is involved in CRC growth and liver metastasis. Therefore, MT2A and MST1 may be potential therapeutic targets for patients with CRC, especially those with liver metastases.

Development and Validation of a Novel Hypoxia Score for Predicting Prognosis and Immune Microenvironment in Rectal Cancer.

Hypoxia plays a major role in various tumor types. However, few studies have concentrated on the prognostic model of hypoxia-related genes in rectal cancer and the effect of hypoxia on neutrophil-mediated immunosuppression. We performed Kaplan-Meier analysis, random survival forest analysis, and Cox regression analysis on 342 hypoxia-related genes, constructed hypoxia score in the Gene Expression Omnibus (GEO) cohort, and verified them in the Cancer Genome Atlas (TCGA) cohort. Then the patients were divided into two groups according to the risk level. The overall survival rate of the high-risk (HRisk) group was significantly higher than that of the low-risk (LRisk) group (GEO, p < 0.001; TCGA, p = 0.016). Through receiver operating characteristic and decision curve analysis, the nomogram based on hypoxia score has excellent prediction ability. Functional enrichment analysis showed that hypoxia, metastasis, inflammation, immunity, and other related pathways were enriched. The HRisk group was associated with lower tumor purity, higher immune and stromal score, higher neutrophils, and lower activated memory CD4 + T cells. More importantly, the checkpoint of neutrophil-mediated immunosuppression increased in the HRisk group. In conclusion, a hypoxia score based on 5 hypoxia-related genes can be used to predict the prognosis of rectal cancer and ANLN with a cancer-suppressing effect and SRPX (Sushi Repeat Containing Protein X-Linked) with a cancer-promoting effect may be potential therapeutic targets for rectal cancer.

UXT, a novel DNMT3b-binding protein, promotes breast cancer progression via negatively modulating lncRNA MEG3/p53 axis.

Overexpressed ubiquitously expressed transcript (UXT) in breast tumors and derived cell lines modulated the transcriptional activity of estrogen receptor alpha. However, how UXT exerts its biological functions in the tumorigenicity of breast cancer remains largely unknown. Expressions of UXT and maternally expressed gene 3 (MEG3) were examined by qRT-PCR and Western blot. The capacity of cell proliferation, apoptosis, migration, and invasion was assessed using CCK-8, flow cytometry, and transwell assays. Methylation-specific PCR (MS-PCR) was employed to evaluate the methylation of the MEG3 imprinting control region. Co-immunoprecipitation was performed to verify the UXT/DNMT3b interaction. RNA immunoprecipitation (RIP) was subjected to assess the regulation of MEG3 on p53 activity. A xenograft tumor model was further conducted to certify the molecular mechanism. UXT was upregulated, while MEG3 was downregulated in breast cancer tissues and cell lines. UXT knockdown or MEG3 overexpression inhibited cell proliferation, promoted apoptosis, and weakened cell migration and invasion. Hypermethylation of the MEG3 imprinting control region was modulated by highly expressed DNMT3b. UXT inhibited MEG3 expression via recruiting DNMT3b to its imprinting control region. MEG3 positively regulated p53 activity. UXT negatively regulated the MEG3/p53 axis in a DNMT3b-dependent manner to promote tumor growth. UXT, a novel DNMT3b-binding protein, aggravates the progression of breast cancer through MEG3/p53 axis.

Facile Preparation of Drug-Releasing Supramolecular Hydrogel for Preventing Postoperative Peritoneal Adhesion.

Hydrogels have attracted widespread attention for breaking the bottlenecks faced during facile drug delivery. To date, the preparation of jelly carriers for hydrophobic drugs remains challenging. In this study, by evaporating ethanol to drive the formation of hydrogen bonds, hydrophilic poly(vinyl alcohol) (PVA) and certain hydrophobic compounds [luteolin (LUT), quercetin (QUE), and myricetin (MYR)] were rapidly prepared into supramolecular hydrogel within 10 min. The gelation performance of these three hydrogels changed regularly with the changing sequence of LUT, QUE, and MYR. An investigation of the gelation pathway of these hybrid gels reveals that the formation of this type of gel follows a simple supramolecular self-assembly process, called "hydrophobe-hydrophile crosslinked gelation". Because the hydrogen bond between PVA and the drug is noncovalent and reversible, the hydrogel has good plasticity and self-healing properties, while the drugs can be controllably released by tuning the output stimuli. Using a rat sidewall-cecum abrasion adhesion model, the as-prepared hydrogel was highly efficient and safe in preventing postsurgical adhesion. This work provides a useful archetypical template for researchers interested in the efficient delivery and controllable release of hydrophobic drugs.

Endostatin in fibrosis and as a potential candidate of anti-fibrotic therapy.

Fibrotic diseases pose significant clinical challenges due to their broadness and complexity. Thus, a better understanding of fibrogenesis and the development of more effective treatments is imperative. Recent evidence suggests a significant antifibrotic potential of an endogenous glycoprotein, endostatin. While endostatin has been widely studied for its role as an anticancer adjuvant by inhibiting tumor angiogenesis, its possible implication in fibrosis remains largely unclear. Here, we review the role of endostatin in various cellular processes and highlight its antifibrotic activity. We hypothesize that endostatin conveys a homeostatic function in the process of fibrosis by regulating (a) TGF-ß1 and its downstream signaling; (b) RhoA/ROCK pathway; (c) NF-κB signaling pathway; (d) expression of EGR-1; (e) PDGF/PDGFR pathway; (f) autophagy-related pathways; (g) pathways associated with cell proliferation and apoptosis. Finally, we propose a schematic model of the antifibrotic roles and mechanisms of endostatin; also, we outline future research directions of endostatin and aim to present a potential therapeutic approach for fibrosis.

Rosmarinic acid inhibits migration, invasion, and p38/AP-1 signaling via miR-1225-5p in colorectal cancer cells.

Elucidating the molecular mechanism of the migration and invasion is critical for identifying novel therapeutic targets and may significantly improve the prognosis of colorectal cancer. Emerging evidence suggests an involvement of dysregulated microRNAs in the process of tumorigenesis. Here, we show that miR-1225-5p prevents migration and invasion of colorectal cancer cells. Overexpression of miR-1225-5p significantly decreases the expression of Matrix Metalloproteases (MMPs)-1, 3, and 9. Knockdown of miR-1225-5p elevates ROS level via regulating Keap1/Nrf2 pathway. Furthermore, miR-1225-5p attenuates IL-17A-induced p38/AP-1-signaling pathway by suppressing IL-17RA expression. We also examined the biological effects of Rosmarinic acid (RA) on metastatic colorectal cancer cells. RA inhibited EMT via the p38/AP-1 signaling, and miR-1225-5p is essential for RA-mediated anti-metastatic effects.