A lysosome-targeted near-infrared photosensitizer for photodynamic therapy and two-photon fluorescence imaging.

Organelle-targeted two-photon near-infrared photosensitizers are highly desirable for photodynamic therapy (PDT) of cancer. Herein, in this contribution, we have developed a 2-dicyanomethylenethiazole-based D-π-A structured near-infrared photosensitizer (TTR). TTR exhibits near-infrared emission (704 nm), a large Stokes shift (200 nm), and smaller ΔES1-T1 (the energy gap between S1 and T1) (0.717 eV). In vitro results show that TTR can specifically target lysosomes in living cells for near-infrared fluorescence imaging. With efficient ROS generation, excellent biocompatibility, two-photon imaging capability, and depth imaging (21 µm in vitro and 210 µm in vivo), TTR can effectively kill tumor cells and inhibit the growth of subcutaneous tumors. The hematoxylin-eosin (H&E) staining and blood biochemical parameter results further prove the biocompatibility of TTR. Hence, TTR can be a promising photosensitizer for PDT.

microRNA-124 inhibits stem-like properties and enhances radiosensitivity in nasopharyngeal carcinoma cells via direct repression of expression of JAMA.

Cancer stem cells (CSCs) are a source of tumour recurrence in patients with nasopharyngeal carcinoma (NPC); however, the function of microRNA-124 (miR-124) in NPC CSCs has not been clearly defined. In this study, we investigated the role of miR-124 in NPC CSCs. qRT-PCR was performed to measure miR-124 expression in NPC tissues and cell lines and the effects of miR-124 on stem-like properties and radiosensitivity of NPC cells measured. Luciferase reporter assays and rescue experiments were used to investigate the interaction of miR-124 with the 3'UTR of junctional adhesion molecule A (JAMA). Finally, we examined the effects of miR-124 in an animal model and clinical samples. Down-regulation of miR-124 was detected in cancer tissues and was inversely associated with tumour stage and lymph node metastasis. Overexpression of miR-124 inhibited stemness properties and enhanced radiosensitivity of NPC cells in vitro and in vivo via targeting JAMA. Up-regulation of miR-124 was correlated with superior overall survival of patients with NPC. Our study demonstrates that miR-124 can inhibit stem-like properties and enhance radiosensitivity by directly targeting JAMA in NPC. These findings provide novel insights into the molecular mechanisms underlying therapy failure in NPC.

Development of a high-precision bladder hyperthermic intracavitary chemotherapy device for bladder cancer and pharmacokinetic study.

BACKGROUND: Bladder hyperthermic intracavitary chemotherapy (HIVEC) has good effectiveness for bladder cancer, but conventional HIVEC systems lack precision and convenient application. To test the safety of a new HIVEC device (BR-TRG-II-type) in pigs and to perform a preliminary clinical trial in patients with bladder cancer. METHODS: This device was tested on six pigs to optimize the temperature and time parameters. Then, 165 patients (HIVEC after transurethral resection (TUR), n = 128; or HIVEC, n = 37) treated between December 2006 and December 2016 were recruited. Mitomycin C (MMC) was the chemotherapeutic agent. A serum pharmacokinetic study was performed. The primary endpoints were tumor recurrence, disease-free survival (DFS), and cumulative incidence rate (CIR) during follow-up. The adverse effects were graded. RESULTS: The animal experiment showed that 45 °C for 1 h was optimal. HIVEC was successful, with the infusion tube temperature stably controlled at about 45 °C, and outlet tube temperature of about 43 °C in all patients, for three sessions. Serum MMC levels gradually increased during HIVEC and decreased thereafter. The mean DFS was 39 ± 3.21 months (ranging from 8 to 78 months), and the DFS rate was 89.1% during follow-up. No adverse events occurred. CONCLUSION: The use of the BR-TRG-II-type HIVEC device is feasible for the treatment of bladder cancer. Future clinical trials in patients with different stages of bladder cancer will further confirm the clinical usefulness of this device. TRIAL REGISTRATION: chictr.org.cn: ChiCTR1900022099 (registered on Mar. 252,019). Retrospectively registered.

BRD4 promotes gastric cancer progression through the transcriptional and epigenetic regulation of c-MYC.

Although the significance of BRD4 in the epigenetic memory and cancer genesis has been intensively investigated, little is known about its function and potential roles during the generation and progression of gastric cancer. We report here that BRD4 increases the proliferation and represses the apoptosis of gastric cancer cells through activating c-MYC via transcriptional and epigenetic regulation mechanisms. Expression analyses in both small and large cohort of sample show that BRD4 is highly expressed in gastric cancer tissues/cells when compared with the adjacent non-tumor tissues/normal cells. We also find a positive correlation between the expression of BRD4 and c-MYC in patient samples. The repression of BRD4 by siRNAs leads to the down-regulation of c-MYC in gastric cancer cells. Chromatin immunoprecipitation-qPCR and luciferase assays show that BRD4 binds to and coordinately activates c-MYC promoter, indicating that c-MYC is transcriptional target of BRD4 and BRD4 regulates its basal expression. Further evidence show that the histone acetylation inhibitor reduces the binding of BRD4 as well as the histone activation level on c-MYC promoter, and leads to the down-regulation of c-MYC, suggesting that BRD4 regulates the expression of c-MYC through epigenetic mechanism. Functionally, the suppression of BRD4 leads to growth inhibition and apoptosis in gastric cancer cells. Force expression of c-MYC alongside with BRD4 repression rescue the anti-cancer effects caused by BRD4 repression. Collectively, our data not only uncovered the mechanism of BRD4 in regulating the proliferation of gastric cancer cells but also provides a new therapeutic strategy for this type of cancer.

Cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion for the treatment of gastric cancer: A single-centre retrospective study.

AIM: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemoperfusion (HIPEC) is the treatment regime most likely to achieve prolonged survival in patients with peritoneal carcinomatosis from gastroenteric cancer. To date, few publications have focused on the treatment of patients with gastric cancer alone. Several controversies remain unsolved, including the safety and effectiveness of the CRS-HIPEC combination regime, particularly in cases where HIPEC is used as adjuvant treatment after CRS. Therefore, in the current study, we aimed to evaluate the safety and effectiveness of CRS combined with HIPEC in patients with gastric cancer. METHOD: Data from 231 patients with a median age of 55.1 years treated with the CRS-HIPEC combination regime between January 2009 and December 2014 were retrospectively reviewed. All patients underwent the combination therapy (mean of 2.4 cycles per patient, range, 1 to 4 cycles). RESULTS: Median overall survival was 37.0 months, with 1-, 2- and 3-year survival rates recorded as 83.4%, 68.5%, and 38.7%, respectively. The serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) were significantly decreased after combination therapy in the completeness of cytoreduction (CCR)-0 and CCR-1 groups, while no significant changes observed in marker levels were observed in the CC ≥2 group. The post-operative morbidity and mortality rates were 6.9% and 0.9%, respectively. Multivariate analysis revealed low TNM tumour stage, ascites condition and CCR score as independent predictors for better survival. CONCLUSION: In view of the acceptable morbidity and mortality rates we propose that CRS combined with HIPEC presents an effective and safe treatment modality for patients with gastric cancer, especially in cases where optimal cytoreduction is achieved before the HIPEC procedure.

Thermo-chemotherapy Induced miR-218 upregulation inhibits the invasion of gastric cancer via targeting Gli2 and E-cadherin.

Thermo-chemotherapy has been proven to reduce the invasion capability of cancer cells. However, the molecular mechanism underlying this anti-invasion effect is still unclear. In this study, the role of thermo-chemotherapy in the inhibition of tumor invasion was studied. The results demonstrated that expression of miR-218 was downregulated in gastric cancer tissues, which had a positive correlation with tumor invasion and metastasis. In vitro thermo-chemotherapy increased miR-218 expression in SGC7901 cells and inhibited both proliferation and invasion of cancer cells. Gli2 was identified as a downstream target of miR-218, and its expression was negatively regulated by miR-218. The thermo-chemotherapy induced miR-218 upregulation was also accompanied by increasing of E-cadherin expression. In conclusion, the present study indicates that thermo-chemotherapy can effectively decrease the invasion capability of cancer cells and increase cell-cell adhesion. miR-218 and its downstream target Gli2, as well as E-cadherin, participate in the anti-invasion process.

Hsa_circ_0051908 Promotes Hepatocellular Carcinoma Progression by Regulating the Epithelial-Mesenchymal Transition Process.

Materials and Methods: Hsa_circ_0051908 expression was determined using RT-qPCR. HCC cell proliferation, apoptosis, invasion, and migration were assessed using CCK-8 assay, EdU staining, TUNEL staining, flow cytometry, and transwell assay. The molecular mechanism was analyzed using western blotting. In addition, the role of hsa_circ_0051908 in tumor growth was evaluated in vivo. Results: Hsa_circ_0051908 expression was increased in both HCC tissues and cell lines. The proliferation, migration, and invasion of HCC cells were significantly decreased after hsa_circ_0051908 knockdown, while cell apoptosis was notably increased. Furthermore, we found that hsa_circ_0051908 silencing downregulated vimentin and Snail and upregulated E-cadherin. In vivo, hsa_circ_0051908 silencing significantly inhibited the growth of the tumor. Conclusions: Our data provide evidence that hsa_circ_0051908 promotes HCC progression partially by mediating the epithelial-mesenchymal transition process, and it may be used for HCC treatment.

Curcumol Inhibits the Progression of Hepatocellular Carcinoma by Regulating the Expression of hsa_circ_0028861.

Background: Hsa_circ_0028861, a newly discovered serum exosome circular RNA (circRNA), is greatly reduced in the serum of patients with hepatocellular carcinoma (HCC). However, the exact role of hsa_circ_0028861 in the progression of liver cancer is still unknown. Materials and Methods: Thirty patients with HCC were enrolled in this study. Hsa_circ_0028861 expression was explored via real-time polymerase chain reaction (PCR) assay. The influence of curcumol on HCC cells were tested using CCK-8 assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, cell wound healing assay, and migration assay, respectively. The related mechanism was determined by Western blot. A xenograft tumor model was constructed, and mice were administrated with curcumol. Results: The expression of hsa_circ_0028861 in tumor tissues was elevated of patients with HCC and in HCC cells. Curcumol treatment decreased the expression of hsa_circ_0028861 in HCC cells. Curcumol treatment could largely suppress the viability, proliferation, and migration of HCC cells by reducing hsa_circ_0028861 expression and mediating the epithelial-mesenchymal transition (EMT) process. Curcumol also effectively restrained tumor growth in the HCC mice model. Conclusions: Curcumol exerted an inhibitory role in HCC progression by downregulating hsa_circ_0028861 expression and mediating the EMT process, which provides evidence for screening new therapeutic targets and drug therapies for HCC treatment.

Meta-Structured Covalent Organic Framework Nanocoatings with Active and Angle-Independent Structural Coloration.

High-performance multifunctional nanocoatings not only protect and enhance substrate materials but also offer additional functionalities. This demands a sophisticated coordination of the coating's inherent properties and microstructural features. Here, a multifunctional active nanocoating via meta-structural engineering of covalent organic framework (COF) deposition materials is presented. This COF nanocoating, characterized by well-defined micropores (1-2 nm), meta-structured textures (30-300 nm), tailored thickness (100-300 nm), and good uniformness, showcases a unique combination of angle-independent structural coloration and ultrafast responsiveness to gaseous stimuli. Remarkably, it demonstrates good compatibility with a wide range of inert substrate materials, from rigid ones like glass and metal to flexible elastomers and nanomaterial films of various shapes and sizes. This versatility enables the facile development of devices that can optically report information about their environments. Examples include chemically active coatings with ultrafast (≈10 ms) color-changing behaviors and programmable actuation behaviors upon exposure to gaseous stimuli, and mechanically active coatings that can detect substrate strain up to 50% yet maintain structural robustness and consistent coloration hue. It is believed that meta-structural engineering of COF nanocoatings on inert substrates can enable them to respond to environmental stimuli, potentially indicating a new trend in developing multifunctional materials and smart devices.

Influencing Factors of Healthy Aging Risk Assessed Using Biomarkers: A Life Course Perspective.

Assessing individual risks of healthy aging using biomarkers and identifying associated factors have become important areas of research. In this study, we conducted a literature review of relevant publications between 2018 and 2023 in both Chinese and English databases. Previous studies have predominantly used single biomarkers, such as C-reactive protein, or focused on specific life course stages and factors such as socioeconomic status, mental health, educational levels, and unhealthy lifestyles. By summarizing the progress in this field, our study provides valuable insights and future directions for promoting healthy aging from a life course perspective.

Vacuolar protein sorting-associated protein 72 homolog (VPS72) binding to lysine acetyltransferase 5 (KAT5) promotes the proliferation, invasion and migration of hepatocellular carcinoma through regulating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway.

Hepatocellular carcinoma, a fatal malignancy that occurs in the liver, poses a major public health challenge. This paper attempted to clarify the role and mechanism of vacuolar protein sorting-associated protein 72 homolog (VPS72) in the progression of hepatocellular carcinoma. Firstly, VPS72 expression in hepatocellular carcinoma tissues and the prognostic correlation were analyzed by GEPIA2 database. Western blotting and RT-qPCR assays were used to evaluate VPS72 expression in several hepatocellular carcinoma cell lines. Then, cell proliferation was assessed by cell counting kit-8 and colony formation in HuH-7 cells with VPS72 silencing. Measurement of cell invasion and migration by transwell and wound healing assays. Next, the relationship between VPS72 and lysine acetyltransferase 5 (KAT5) was predicted by bioGRID, STRING and GEIPA2 databases, which was confirmed by Co-immunoprecipitation assay. Subsequently, KAT5 was overexpressed to explore whether VPS72 could regulate the progression of hepatocellular carcinoma by binding to KAT5. And the expression of proteins related to PI3K/AKT signaling was tested with western blotting. Results indicated that VPS72 was highly expressed in hepatocellular carcinoma tissues and cell lines and was associated with poor prognosis. VPS72 knockdown inhibited the proliferation, invasion and migration of HuH-7 cells. In addition, VPS72 could bind to KAT5. KAT5 overexpression reversed the suppressive impacts of VPS72 knockdown on the proliferation, invasion and migration in HuH-7 cells. Besides, VPS72 silencing downregulated p-PI3K and p-AKT expression, which was restored by KAT5 overexpression. Collectively, VPS72 binding to KAT5 promotes the progression of hepatocellular carcinoma through the regulation of PI3K/AKT signaling pathway.

A lysosomal targeted NIR photosensitizer for photodynamic therapy and two-photon fluorescence imaging.

The design and synthesis of near-infrared (NIR) emissive fluorophores for the imaging of organelles and photodynamic therapy have received enormous attention. Hence, the development of NIR emissive fluorophores for high-fidelity lysosome targeting, two-photon fluorescence imaging, and the inducing of photo-triggered cancer-cell apoptosis is highly desirable. In this study, a novel lysosome-targeting two-photon fluorescent photosensitizer (TTRh-CN) is prepared and comprehensively investigated. TTRh-CN demonstrates near-infrared (NIR) emission, good biocompatibility, and superior photostability, and it can act as a two-photon fluorescent agent for the clear visualization of living cells and the vascular system within tissue, with deep-tissue penetration abilities. Furthermore, TTRh-CN can efficiently produce ROS in conjunction with lysosomes in situ upon light irradiation, which can damage lysosomes, up-regulate LC3 and Beclin1, increase BAX release, and induce cell apoptosis. The efficacy of TTRh-CN as a photosensitizer is explored in vivo. All these results confirm that TTRh-CN can serve as a potential platform for the two-photon fluorescence imaging of cells/tissue and for organelle-specific photodynamic therapy.

Safety and Effectiveness of High-Precision Hyperthermic Intraperitoneal Perfusion Chemotherapy in Peritoneal Carcinomatosis: A Real-World Study.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been reported to effectively control peritoneal carcinomatosis (PC) in various patient populations, but there is a lack of real-world data. This study aimed to examine the safety and effectiveness of HIPEC in patients with PC in a real-world setting. METHODS: This was a retrospective study of patients with PC treated with the high-precision BR-TRG-I type HIPEC device between December 2006 and December 2016. Vital signs during HIPEC and adverse events were recorded. Effectiveness was evaluated by total objective remission rate (ORR), which was based on ascites' remission 4 weeks after HIPEC. RESULTS: A total of 1,200 patients were included. There were 518 males and 682 females, with a mean age of 58.6 ± 6.5 years (range, 32-76 years). Among the patients, 93.6% of the patients (1123/1200) successfully received the three sessions of HIPEC, 158 had massive ascites. The changes of vital signs during HIPEC were within acceptable ranges, and patients only had a transient fever and abdominal distension. Regarding the HIPEC-related complications, hemorrhage was observed in seven (0.6%) patients, anastomotic leakage in four (0.5%), and intestinal obstruction in eight (0.7%). Nine (0.8%, 9/1200) patients had CTCAE grade IV bone marrow suppression, and three (0.3%, 3/1200) patients had severe renal failure (SRF), which were considered to be drug-related. The ORR of malignant ascites was 95.6% (151/158). CONCLUSION: This real-world study strongly suggests that HIPEC was safe in treating PC patients with a low rate of adverse events and leads to benefits in PC patients with massive malignant ascites.

Knockdown of lncRNA ZNRD1-AS1 suppresses gastric cancer cell proliferation and metastasis by targeting the miR-9-5p/HSP90AA1 axis.

LncRNAs play an important role in a variety of biological processes, such as cancer pathogenesis. The lncRNA zinc ribbon domain containing 1 antisense RNA 1 (ZNRD1-AS1) is a natural antisense transcript of ZNRD1. In this study, we found that ZNRD1-AS1 levels were significantly upregulated in gastric cancer tissues compared to those in adjacent healthy gastric tissues. ZNRD1-AS1 levels were correlated with lymph node metastasis, distal metastasis, and TNM stage, but were not correlated with age and sex. ZNRD1-AS1 knockdown suppressed cell proliferation, migration, and invasion, and promoted apoptosis. ZNRD1-AS1 overexpression had the opposite effect. ZNRD1-AS1 knockdown suppressed tumor growth and pulmonary metastasis in a nude mouse model ZNRD1-AS1 can bind to miR-9-5p and ZNRD1-AS1 knockdown can decrease the protein level of heat shock protein 90 alpha family class A member 1 (HSP90AA1), which is the target of miR-9-5p. The miR-9-5p inhibitor rescued the effect of ZNRD1-AS1 knockdown, and the mutant of miR-9-5p binding site on ZNRD1-AS1 sequence blocked the effect of ZNRD1-AS1 overexpression. In conclusion, ZNRD1-AS1 levels were upregulated in gastric cancer tissues, and knockdown of ZNRD1-AS1 suppressed gastric cancer cell proliferation and metastasis by targeting the miR-9-5p/HSP90AA1 axis. Our findings provide novel insights into the mechanism underlying the role of ZNRD1-AS1 in gastric cancer.

Light-Induced Reactive Oxygen Species (ROS) Generator for Tumor Therapy through an ROS Burst in Mitochondria and AKT-Inactivation-Induced Apoptosis.

Mitochondria are identified as a valuable target for cancer therapy owing to their primary function in energy supply and cellular signal regulation. Mitochondria in tumor cells are depicted by excess reactive oxygen species (ROS), which lead to numerous detrimental results. Hence, mitochondria-targeting ROS-associated therapy is an optional therapeutic strategy for cancer. In this contribution, a light-induced ROS generator (TBTP) is developed for evaluation of the efficacy of mitochondria-targeting ROS-associated therapy and investigation of the mechanism underlying mitochondrial-injure-mediated therapy of tumors. TBTP serves as an efficient ROS generator with low cytotoxicity, favorable biocompatibility, excellent photostability, mitochondria-targeted properties, and NIR emission. In vivo and in vitro experiments reveal that TBTP exhibits effective anticancer potential. ROS generated from TBTP could destroy the integrity of mitochondria, downregulate ATP, decrease the mitochondrial membrane potential, secrete Cyt-c into cytoplasm, activate Caspase-3/9, and induce cell apoptosis. Moreover, RNA-seq analysis highlights that an ROS burst in mitochondria can kill tumor cells via inhibition of the AKT pathway. All these results prove that mitochondrial-targeted ROS-associated therapy hold great potential in cancer therapy.

Cytoreductive surgery and HIPEC for malignant ascites from colorectal cancer - a randomized study.

INTRODUCTION: The efficacy of different timings of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in controlling malignant ascites caused by peritoneal carcinomatosis of colorectal cancer (CRC) is not well defined. The study aims to investigate the clinical efficacy and safety of different timings of CRS with HIPEC for malignant ascites caused by peritoneal carcinomatosis from CRC. MATERIALS AND METHODS: This was a preliminary randomized controlled study performed at the Intracelom Hyperthermic Perfusion Therapy Center of the Cancer Hospital of Guangzhou Medical University (China) from December 2008 to December 2016. The patients were randomized to: CRS, followed by HIPEC (CRS+HIPEC; n = 14), and ultrasound-guided HIPEC, followed by CRS 1 to 2 weeks later (HIPEC+ delayed cytoreductive surgery (dCRS) group, n = 14). The endpoints were complete remission rate of ascites, successful complete CRS rate, and overall survival. RESULTS: Malignant ascites in all patients showed complete remission; the total effective rate was 100%. Complete CRS was not feasible in any patient. The median follow-up of the 2 groups was 41.9 and 42.3 months in the CRS+HIPEC and HIPEC+dCRS groups, respectively. Overall survival was 14.5 (95%CI: 7-19 months) and 14.3 months (95%CI: 4-21 months) (P > .05). The adverse effects of HIPEC were manageable. CONCLUSIONS: CRS+HIPEC and HIPEC+dCRS have the same efficacy in controlling malignant ascites caused by CRC and peritoneal carcinomatosis. The timing of CRS and HIPEC does not prolong the survival of patients with peritoneal carcinomatosis from CRC, even when a complete CRS is not feasible.

A thermosensitive nanoplatform for photoacoustic imaging and NIR light triggered chemo-photothermal therapy.

Temperature-sensitive liposomes (TSLs) have received constant attention due to the release of contents around the physiological temperature, which holds great potential in the treatment of tumors. However, the development of TSLs is limited by the long-term biotoxicity and low photothermal conversion efficiency of heat-generation materials. In this study, we develop a new D-A (donor-acceptor) structure NIR absorbing dye (C720) which exhibits a high photothermal conversion efficiency (62%), good photostability, and photothermal reproducibility. Then C720 is doped in the lipid bilayer and DOX (doxorubicin) is wrapped in the core of temperature sensitive liposomes to construct a C720 and DOX-loaded thermosensitive nanoplatform (CDTSL). The as-prepared CDTSL achieves NIR light controlled drug release and can be applied for photoacoustic imaging. In vitro and in vivo studies confirm that CDTSL exhibits high tumor suppressive efficiency by synergistic photothermal therapy and chemotherapy. Our research provides fundamental insights for the rational design and preparation of a promising nanoplatform for photoacoustic imaging and chemo-photothermal therapy.

LncRNA AC093818.1 accelerates gastric cancer metastasis by epigenetically promoting PDK1 expression.

Gastric cancer (GC) is a highly prevalent type of metastatic tumor. The mechanisms underlying GC metastasis are poorly understood. Some long noncoding RNAs (lncRNAs) reportedly play key roles in regulating metastasis of GC. However, the biological roles of five natural antisense lncRNAs (AC093818.1, CTD-2541M15.1, BC047644, RP11-597M12.1, and RP11-40A13.1) in GC metastasis remain unclear. In this study, the expression of these lncRNAs was measured by quantitative reverse transcription-polymerase chain reaction. Migration and invasion were evaluated by wound-healing and the Transwell assay, respectively. Stable cells were injected into the tail veins of nude mice. Sections of collected lung and liver tissues were stained using hematoxylin and eosin. Protein expression was analyzed by western blot. RNA immunoprecipitation (RIP) assay was used to verify whether the STAT3 and SP1 transcription factors bound to AC093818.1 in GC cells. Expression levels of the five lncRNAs, especially AC093818.1, were significantly upregulated in metastatic GC tissues relative to those in nonmetastatic GC tissues. AC093818.1 expression was correlated with invasion, lymphatic metastasis, distal metastasis, and tumor-node-metastasis stage. AC093818.1 expression was highly sensitive and specific in the diagnosis of metastatic or nonmetastatic GC. AC093818.1 overexpression promoted GC migration and invasion in vitro and in vivo. AC093818.1 overexpression increased PDK1, p-AKT1, and p-mTOR expression levels. AC093818.1 silencing decreased these expressions. AC093818.1 bound to transcription factors STAT3 and SP1, and SP1 or STAT3 silencing could alleviated the effect of AC093818.1 overexpression. The data demonstrate that lncRNA AC093818.1 accelerates gastric cancer metastasis by epigenetically promoting PDK1 expression. LncRNA AC093818.1 may be a potential therapeutic target for metastatic GC.

Thermo-chemotherapy inhibits the proliferation and metastasis of gastric cancer cells via suppression of EIF5A2 expression.

PURPOSE: Thermo-chemotherapy (TCT) is a new approach for the treatment of cancer that combines chemotherapy with thermotherapy. In the present study, we investigated the relationship between eukaryotic translation initiation factor 5A2 (EIF5A2) and TCT sensitivity in gastric cancer (GC) to further illuminate the molecular mechanism underlying the effect of TCT on GC. METHODS: A TCT cell model was constructed, and EIF5A2 was silenced or overexpressed by infection with a lentivirus expressing either EIF5A2 or EIF5A2 shRNA. Then, RT-qPCR, Western blotting, and immunohistochemistry assays were performed to evaluate the changes in the expression levels of EIF5A2, c-myc, vimentin, and E-cadherin. Cell proliferation and xenograft assays were conducted to evaluate the effect on cell proliferation. Finally, wound-healing and Transwell invasion assays were performed to evaluate the effects on migration and invasion. RESULTS: TCT reduced EIF5A2 expression at both the mRNA and protein levels. It also inhibited cell proliferation, migration, and invasion, downregulated the expression of c-myc and vimentin, and increased the expression of E-cadherin in both MKN28 and MKN45 cells. Silencing of EIF5A2 enhanced the above effects of TCT on MKN28 and MKN45 cells, while overexpression of EIF5A2 had the opposite effects. In addition, EIF5A2 overexpression weakened the inhibitory effect of TCT on tumor growth in vivo as well as the effects on c-myc, vimentin, and E-cadherin. CONCLUSION: TCT inhibits GC cell proliferation and metastasis by suppressing EIF5A2 expression. Our results provide new insights into our understanding of the molecular mechanism underlying the effects of TCT in GC.

Clinical significance of heat shock proteins in gastric cancer following hyperthermia stress: Indications for hyperthermic intraperitoneal chemoperfusion therapy.

Heat shock proteins (HSPs) are important factors in the response of cancer cells to thermo- and chemotherapy. Transient hyperthermic intraperitoneal chemoperfusion (HIPEC) therapy results in the upregulation of HSP expression, which may compromise the efficacy of additional anticancer treatments. The aim of the present study was to monitor the kinetics of HSP expression in tumor cells and patients with gastric cancer following HIPEC. Thus, in vitro and in vivo experiments were conducted to investigate the expression of two HSP family members, HSP70 and HSP90. Cells from two gastric tumor strains were subjected to HIPEC-mimicking treatment, and HSPs expression was analyzed at specific time points up to 48 h. Serum HSP concentrations were analyzed in patients with gastric cancer who had previously received cytoreductive surgery plus HIPEC treatment. The in vitro experiments indicated a significant elevation of HSP90 expression in gastric adenocarcinoma cells following hyperthermic treatment. However, HSP70 expression increased from 4 h up to 20 h post-exposure and decreased to normal levels 36 h post-exposure. Analysis of HSPs in serum samples collected from 22 patients with gastric cancer confirmed that serum HSP90 and HSP70 levels increased following HIPEC therapy, peaking at 18 h and returning to normal 24 h post-exposure. It is therefore advisable to apply the second round of HIPEC or chemotherapy at least 24 h following the first treatment to minimize any potential thermoresistance and chemoresistance of tumor cells.