CD44 is an adhesion molecule expressed in cancer stem-like cells. Here, we show that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level ...of reduced glutathione (GSH). Human gastrointestinal cancer cells with a high level of CD44 expression showed an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS). Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer. It also induced activation of p38
MAPK, a downstream target of ROS, and expression of the gene for the cell cycle inhibitor p21
CIP1/WAF1. These findings establish a function for CD44v in regulation of ROS defense and tumor growth.
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► CD44v contributes to the reduction of intracellular reactive oxygen species ► CD44v promotes GSH synthesis by interacting with glutamate-cystine transporter xCT ► Variant 8–10 region is required for CD44v-xCT interaction leading to GSH synthesis ► xCT inhibitor sulfasalazine suppresses CD44-dependent cancer cell expansion in vivo
Peritoneal metastasis is a common form of metastasis among advanced gastric cancer patients. In this study, we reported the identification of LIM domain kinase 1 (LIMK1) as a promoter of gastric ...cancer peritoneal metastasis, and its potential to be a therapeutic target of dabrafenib (DAB). Using transcriptomic sequencing of paired gastric cancer peritoneal metastasis, primary tumors, and normal gastric tissues, we first unveiled that LIMK1 is selectively up-regulated in metastatic tumors. Increased LIMK1 in gastric cancer peritoneal metastasis was validated by immunohistochemistry analysis of an independent patient cohort. In vitro functional studies demonstrated that LIMK1 knockout or knockdown significantly inhibited cell migration and invasion of gastric cancer cells. LIMK1 knockout also abrogated peritoneal and liver metastases of gastric cancer cells in nude mice in vivo. Dabrafenib, a small molecule targeting LIMK1, was found to decrease cell migration and invasion of gastric cancer cells in vitro and abolish peritoneal and liver metastasis formation in vivo. Mechanistically, either LIMK1 knockout or Dabrafenib inhibited LIMK1 expression and phosphorylation of its downstream target cofilin. Taken together, our results demonstrated that LIMK1 functions as a metastasis promoter in gastric cancer by inhibiting LIMK1-p-cofilin and that Dabrafenib has the potential to serve as a novel treatment for gastric cancer peritoneal metastasis.
Gastric cancer (GC) is an aggressive disease with one of the highest mortality rates in the world. In the early stage, most patients are asymptomatic and early diagnosis is difficult. Recently, ...cancer stem cells (CSCs) have been highlighted as crucial emerging factors in the initiation or invasiveness of solid tumors. CD133, a CSC marker, is highly expressed in various tumors including gastric cancer. CD133-positive cells showed elevated malignant biological behaviors and CD133 upregulation is related to chemoresistance, cancer relapse, and poor prognosis. CD133 also plays an important role in the progression of tumors and metastasis. This review summarizes the current knowledge of the role of CD133 expression in GC and aims to contribute at identifying promising new strategies for treatment and management of gastric cancer.
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Long non-coding RNAs (lncRNAs), as one of the components of exosomes derived from cancer-associated fibroblasts (CAFs), exhibit a crucial role in the pathogenesis and chemoresistance of gastric ...cancer (GC). Herein, we investigated the role and mechanism of a novel lncRNA disheveled binding antagonist of beta catenin3 antisense1 (DACT3-AS1) and its involvement in GC.
DACT3-AS1 was identified by RNA-sequencing and verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The functional role of DACT3-AS1 in GC was evaluated using in vitro and in vivo experiments including Transwell assay, 5-Ethynyl-2′-deoxyuridine (EdU) assay, immunoblotting, and xenograft tumor mouse model. Dual-luciferase reporter assay was performed to assess the association between genes.
DACT3-AS1 was downregulated and involved in poor prognosis of patients with GC. The results from both in vitro and in vivo experiments showed that DACT3-AS1 suppressed cell proliferation, migration, and invasion through targeting miR-181a-5p/sirtuin 1 (SIRT1) axis. Additionally, DACT3-AS1 was transmitted from CAFs to GC cells mainly via exosomes. Exosomal DACT3-AS1 alleviated xenograft tumor growth. DACT3-AS1 conferred sensitivity of cancer cells to oxaliplatin through SIRT1-mediated ferroptosis both in vitro and in vivo.
CAFs-derived exosomal DACT3-AS1 is a suppressive regulator in malignant transformation and oxaliplatin resistance. DACT3-AS1 could be used for diagnosis and treatment of GC.
The purpose of this study is to compare the surgical, oncologic safety and the nutritional, functional benefit of laparoscopy-assisted pylorus-preserving gastrectomy (LAPPG) with laparoscopy-assisted ...distal gastrectomy (LADG) for middle-third early gastric cancers (EGC).
Of those patients with middle-third EGC, it is still difficult to determine which procedure is better between LADG and LAPPG despite alleged advantages of LAPPG.
For middle-third EGC, a retrospective analysis was performed comparing those who underwent LADG and those who underwent LAPPG. To evaluate surgical and oncologic safety, clinicopathologic differences including the postoperative morbidity, the pattern of lymph node metastasis and recurrence were analyzed. Postoperative protein, albumin, quantification of abdominal fat area using abdomen computed tomography, and the incidence of postoperative gallstone were compared for the evaluation of functional advantages.
The overall postoperative morbidity rate was similar between LADG (n = 176) and LAPPG (n = 116). Delayed gastric emptying was less frequent in LADG than in LAPPG (1.7% vs 7.8%); however, the rates of all the other complications were significantly higher in LADG than in LAPPG (17.0% vs 7.8%). The number of examined lymph nodes and metastatic lymph nodes at each lymph node station was not significantly different and 3-year recurrence-free survival rates were also similar between LADG and LAPPG (98.8% vs 98.2%). Decreases in serum protein and albumin in postoperative 1 to 6 months and abdominal fat area in postoperative 1 year were significantly greater in LADG than in LAPPG. The 3-year cumulative incidence of gallstone was significantly higher in LADG than in LAPPG (6.5% vs 0.0%).
For middle-third EGC, LAPPG can be considered as a better treatment option than LADG in terms of nutritional advantage and lower incidence of gallstone.
Preserving functional capacity is a key element in the care continuum for patients with esophagogastric cancer. Prehabilitation, a preoperative conditioning intervention aiming to optimize physical ...status, has not been tested in upper gastrointestinal surgery to date.
To investigate whether prehabilitation is effective in improving functional status in patients undergoing esophagogastric cancer resection.
A randomized clinical trial (available-case analysis based on completed assessments) was conducted at McGill University Health Centre (Montreal, Quebec, Canada) comparing prehabilitation with a control group. Intervention consisted of preoperative exercise and nutrition optimization. Participants were adults awaiting elective esophagogastric resection for cancer. The study dates were February 13, 2013, to February 10, 2017.
The primary outcome was change in functional capacity, measured with absolute change in 6-minute walk distance (6MWD). Preoperative (end of the prehabilitation period) and postoperative (from 4 to 8 weeks after surgery) data were compared between groups.
Sixty-eight patients were randomized, and 51 were included in the primary analysis. The control group were a mean (SD) age, 68.0 (11.6) years and 20 (80%) men. Patients in the prehabilitation group were a mean (SD) age, 67.3 (7.4) years and 18 (69%) men. Compared with the control group, the prehabilitation group had improved functional capacity both before surgery (mean SD 6MWD change, 36.9 51.4 vs -22.8 52.5 m; P < .001) and after surgery (mean SD 6MWD change, 15.4 65.6 vs -81.8 87.0 m; P < .001).
Prehabilitation improves perioperative functional capacity in esophagogastric surgery. Keeping patients from physical and nutritional status decline could have a significant effect on the cancer care continuum.
ClinicalTrials.gov Identifier: NCT01666158.
To investigate the anti-tumor activities of WZ35 and its possible molecular mechanism, bioinformatics analysis and the hematoxylin-eosin (HE) staining were applied to evaluate the ...Yes-associated-protein (YAP) level in gastric cancer. Cell counting kit-8 (CCK-8) was used to examine cell viability. Apoptosis was determined by flow cytometry analysis. Seahorse bioenergetics analyzer was used to investigate the alteration of oxygen consumption and aerobic glycolysis rate. SiRNA transfection was applied to silence endogenous YAP. Western blot was performed to detect indicated proteins. We found that treatment of gastric cancer cells with WZ35 exerted stronger anti-tumor activities than curcumin. Mechanistically, our research showed that WZ35 inhibited glycolysis, and induced reactive oxygen species (ROS) generation, resulting in Jun N-terminal Kinase (JNK) activation through downregulation of YAP in gastric cancer cells. ROS mediated YAP downregulation and JNK activation was regulated by glycolysis. Abrogation of ROS production markedly attenuated WZ35 induced anti-tumor activities as well as YAP downregulation and JNK activation. Similarly, the JNK inhibitor significantly reversed WZ35 induced anti-tumor activities in gastric cancer cells. Our study reveals a novel anti-gastric cancer mechanism of WZ35 by inhibiting glycolysis through the ROS-YAP-JNK pathway. WZ35 might be a potential therapeutics for the treatment of gastric cancer.
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•Curcumin analogue WZ35 inhibits gastric cancer cell growth.•ROS mediated YAP and JNK activation was regulated by glycolysis.•Glycolysis throught ROS-YAP-JNK pathway might be a potential therapeutic target of gastric cancer.
Background
This study aimed to investigate the association between gastrectomy and endoscopic resection for gastric cancer and the subsequent tuberculosis incidence.
Methods
We conducted a nationwide ...matched cohort study using data from the Korea National Health Insurance Service from 2013 to 2019. We created two cohorts: patients who underwent gastrectomy and those who had endoscopic resection. Each patient was matched 1:1 with an unexposed individual based on index year, age, sex, income, and various comorbidities. The primary outcome was the incidence of tuberculosis during the follow-up period.
Results
Our study comprised 90,886 gastrectomy patients and 46,759 endoscopic resection patients. The tuberculosis incidence was significantly higher in the gastrectomy group compared to its matched non-gastrectomy group (IRR 1.69, 95% CI 1.43–1.99, p < .001). In contrast, there was no significant difference in tuberculosis incidence between the endoscopic resection group and its matched non-resection group (IRR 0.95, 95% CI 0.75–1.19, p = 0.627). The Kaplan–Meier cumulative incidence also did not differ between the two groups. However, tuberculosis incidence significantly increased in the first year after endoscopic resection.
Conclusion
Gastrectomy for gastric cancer is associated with a higher incidence of subsequent tuberculosis, while no significant association was observed for endoscopic resection. However, tuberculosis incidence increases significantly during the first year after endoscopic resection.
CpG island promoter methylation of tumor suppressor genes is one of the most characteristic abnormalities in EBV-associated gastric carcinoma (GC). Aberrant promoter methylation and expression loss ...of PTEN were evaluated in cancer tissues of GC by methylation-specific PCR and immunohistochemistry, respectively, showing that both abnormalities occurred concurrently in EBV-associated GC. PTEN abnormalities were reiterated in GC cell lines MKN-1 and MKN-7 infected with recombinant EBV, and DNA methyltransferase 1 (DNMT1) was commonly overexpressed in both cell lines. Stable and transient transfection systems in MKN-1 similarly showed that viral latent membrane protein 2A (LMP2A) up-regulated DNMT1, leading to an increase in methylation of the PTEN promoter. Importantly, the level of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) increased in the nuclei of LMP2A-expressing GC cells, and knockdown of STAT3 counteracted LMP2A-mediated DNMT1 overexpression. Immunohistochemistry for both pSTAT3 and DNMT1 showed diffuse labeling in the nuclei of the cancer cells in GC tissues, especially in EBV-associated GC. Taken together, LMP2A induces the phosphorylation of STAT3, which activates DNMT1 transcription and causes PTEN expression loss through CpG island methylation of the PTEN promoter in EBV-associated GC. LMP2A plays an essential role in the epigenetic abnormalities in host stomach cells and in the development and maintenance of EBV-associated cancer.
Backgrounds
Laparoscopy-assisted distal gastrectomy (LADG) for gastric cancer is safe and feasible. In contrast, no prospective study evaluating the safety and efficacy of laparoscopy-assisted total ...gastrectomy (LATG) or laparoscopy-assisted proximal gastrectomy (LAPG) has been completed. We conducted a single-arm confirmatory trial to evaluate the safety of LATG/LAPG for clinical stage I (T1N0/T1N1/T2N0) proximal gastric cancer.
Methods
The extent of lymphadenectomy was selected based on the Japanese Gastric Cancer Treatment Guidelines. The mini-laparotomy incision was required to be ≤ 6 cm. The primary endpoint was the proportion of grade 2–4 (CTCAE ver. 4.0) esophagojejunal anastomotic leakage. The planned sample size was 245 considering a threshold of 8% and one-sided alpha of 2.5%.
Results
Between April 2015 and February 2017, 244 eligible patients were enrolled. LATG/LAPG was performed in 195/49. The proportion of conversions was 1.7%. Clinical T1N0/T1N1/T2N0 was 212/9/23. The extents of lymphadenectomy were as follows: D1+: 229; D2: 15. The median operation time was 309 min (IQR 265–353). The median blood loss was 30 ml (IQR 10–86). Grade 2–4 esophagojejunal anastomotic leakage was 2.5% (6/244; 95% CI 0.9–5.3). The overall proportion of in-hospital grade 3–4 adverse events was 29% (71/244). The proportions of intraabdominal abscess and pancreatic fistula were 3.7% and 2.0%, respectively. There were no treatment-related deaths.
Conclusions
This trial confirmed the safety of LATG/LAPG. After the non-inferiority of LADG is confirmed in our phase III trial (JCOG0912), LATG/LAPG is expected to be established as one of the standard treatments for clinical stage I gastric cancer.
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