GDF15 Promotes Cell Growth, Migration, and Invasion in Gastric Cancer by Inducing STAT3 Activation.

Growth differentiation factor 15 (GDF15) has been reported to play an important role in cancer and is secreted and involved in the progression of various cancers, including ovarian cancer, prostate cancer, and thyroid cancer. Nevertheless, the functional mechanism of GDF15 in gastric cancer is still unclear. Immunohistochemical staining was performed to estimate the expression of GDF15 in 178 gastric cancer tissues. The biological role and action mechanism of GDF15 were investigated by examining the effect of GDF15 knockdown in AGS and SNU216 gastric cancer cells. Here, we report that the high expression of GDF15 was associated with invasion depth (p = 0.002), nodal involvement (p = 0.003), stage III/IV (p = 0.01), lymphatic invasion (p = 0.05), and tumor size (p = 0.049), which are related to poor survival in gastric cancer patients. GDF15 knockdown induced G0/G1 cell cycle arrest and remarkably inhibited cell proliferation and reduced cell motility, migration, and invasion compared to the control. GDF15 knockdown inhibited the epithelial-mesenchymal transition by regulating the STAT3 phosphorylation signaling pathways. Taken together, our results indicate that GDF15 expression is associated with aggressive gastric cancer by promoting STAT3 phosphorylation, suggesting that the GDF15-STAT3 signaling axis is a potential therapeutic target against gastric cancer progression.

Decursin inhibits tumor progression in head and neck squamous cell carcinoma by downregulating CXCR7 expression in vitro.

CXC chemokine receptor 7 (CXCR7) is frequently overexpressed in cancer and plays a significant role in tumor growth and metastasis. Consequently, inhibition of CXCR7 is important for treatment strategies. However, little is known concerning the biological role of CXCR7 and its underlying mechanisms in head and neck squamous cell carcinoma (HNSCC). The present study investigated the role of CXCR7 in HNSCC, as well as the effects of decursin, a pyranocoumarin compound isolated from Angelica gigas Nakai, on CXCR7 and its downstream signaling. Expression levels of CXCR7 in HNSCC cells were examined using flow cytometry, reverse transcriptase PCR, western blot analysis, and immunofluorescence. The effects of CXCR7 on cell proliferation, migration, and invasion were studied using CCK­8, gap closure, and transwell assays. The results revealed that decursin significantly reduced CXCR7 expression and inhibited cell proliferation, migration, and invasion of human HNSCC cell lines. In addition, decursin induced G0/G1 cell cycle arrest in CXCR7­overexpressing cells and decreased the levels of cyclin A, cyclin E, and CDK2. Furthermore, CXCR7 promoted cancer progression via the STAT3/c­Myc pathway in HNSCC; suppression of CXCR7 with decursin prevented this effect. These results suggest that CXCR7 promotes cancer progression through the STAT3/c­Myc pathway and that the natural compound decursin targets CXCR7 and may be valuable in the treatment of HNSCC.

Small heterodimer partner as a predictor of neoadjuvant radiochemotherapy response and survival in patients with rectal cancer: A preliminary study.

Small heterodimer partner (SHP) plays an essential role in the regulation of innate immune and inflammatory responses. The aim of the present study was to identify whether SHP levels are associated with cancer immunology and treatment outcomes in rectal cancer. SHP expression was analyzed via gene set enrichment analysis and the OncoLnc database. In addition, immunohistochemistry and reverse transcription-quantitative PCR analyses were performed on the tissues of patients with locally advanced rectal cancer, and the associations of SHP expression with the clinicopathological and hematological features or treatment response to preoperative radiochemotherapy (pRCT) were analyzed retrospectively. Furthermore, the present study investigated whether SHP expression correlated with immune infiltration levels and immune checkpoint molecules in rectal cancer. The results revealed that low SHP mRNA expression was significantly associated with an inflammatory response and poor prognosis. The nuclear expression of SHP was associated with clinical N stage, neutrophil count, lymphocyte count, neutrophil-lymphocyte ratio and complete pathologic response following pRCT. The low nuclear expression of SHP was associated with poor overall and distant metastasis-free survival (DMFS). In multivariate analysis, the low nuclear expression of SHP was identified as a significant independent prognostic factor for DMFS and a marginally significant prognostic factor for overall survival in rectal cancer. Furthermore, patients with low SHP expression exhibited higher neutrophil and CD8+ T cell infiltration levels and higher PD-L1 expression in rectal adenocarcinoma. These results indicate that SHP may act as an anti-inflammatory mediator via the regulation of systemic and local immune responses in rectal cancer. Moreover, SHP might be useful a potential marker or therapeutic target in rectal cancer.

Decursin inhibits cell growth and autophagic flux in gastric cancer via suppression of cathepsin C.

Autophagy plays an important role in the survival of cancer cells under stressful conditions, such as nutrient or oxygen deficiency. Therefore, autophagy inhibition is being considered as a novel therapeutic strategy for cancer. Decursin is a natural compound derived from Angelica gigas; it has been used in the treatment of various diseases, including cancer. However, the mechanism by which decursin regulates autophagy in gastric cancer and other carcinomas remains unclear. Here, we demonstrated that decursin reduced the growth and induced cell cycle arrest in gastric cancer cells in vitro. Decursin blocked autophagic flux by reducing the expression of lysosomal protein cathepsin C (CTSC) and attenuating its activity, thereby causing autophagic dysregulation (i.e., accumulation of LC3 and SQSTM1). Decursin also inhibited cell proliferation and cell cycle progression by inhibiting CTSC and E2F3, both of which were linked to gastric cancer aggressiveness. The antitumor effects of decursin were confirmed in vivo. We established spheroid and patient-derived organoid models and found that decursin decreased the growth of spheroids and patient-derived gastric organoids, as well as modulated the expression of CTSC and autophagy-related proteins. Hence, our findings uncovered a previously unknown mechanism by which decursin regulates cell growth and autophagy and suggests that decursin may act as a potential therapeutic agent that simultaneously inhibits cell growth and autophagy.

Pilot Study to Evaluate the Efficacy of Polynucleotide Sodium Compared to Sodium Hyaluronate and Crosslinked Sodium Hyaluronate in Patients with Knee Osteoarthritis.

Degenerative arthritis of the knee joint has become a major social problem worldwide due to population aging. There are several treatment options for knee osteoarthritis, and the intraarticular injection of sodium hyaluronate is commonly selected by many clinicians as a nonsurgical treatment. However, the efficacy of the treatment is controversial. In this pilot study, we aimed to compare polynucleotide sodium (Conjuran®) with sodium hyaluronate (Hyruan Plus®) and 1,4-butanediol diglycidyl ether-crosslinked sodium hyaluronate (Synovian®) in terms of analgesic efficacy after intraarticular injection in patients with knee osteoarthritis. One of the three intraarticular agents was selected according to what agents were available for outpatients when each patient was enrolled in the study. The 15 enrolled patients were subdivided into 3 groups of 5 patients each. Three injections were performed under ultrasound guidance at a 1-week intervals over a total of 3 weeks. The visual analog scale (VAS) score, the Korean version of the Western Ontario and McMaster Universities Arthritis Index (K-WOMAC), the EuroQol five-dimension scale (EQ-5D) score, and the Korean version of the painDETECT Questionnaire (K-PDQ) score were evaluated before injection and at 1, 2, and 6 weeks after the start of the treatment protocol. The primary endpoint was the change in weight-bearing pain at 4 weeks after the last injection. Secondary endpoints included pain at rest and during walking and the K-WOMAC, EQ-5D, and K-PDQ scores. Weight-bearing pain decreased significantly more from pretreatment to 6 weeks after the start of the treatment protocol in the polynucleotide sodium-treated patients than in the patients who were treated with other agents (p = 0.006, one-way ANOVA). There were no significant between-group differences in the other secondary endpoints. No adverse events occurred. In conclusion, polynucleotide sodium could effectively reduce weight-bearing pain in the patients with knee osteoarthritis compared to standard hyaluronic acid viscosupplementation.

Factors Predicting the Success of Adhesiolysis Using a Steerable Catheter in Lumbar Failed Back Surgery Syndrome: A Retrospective Study.

Failed back surgery syndrome (FBSS) is a commonly encountered disease after lumbar surgery. There are many cases where it is difficult to choose a treatment because no specific cause can be found. Nevertheless, according to recent reports, adhesiolysis has shown reasonable evidence. However, considering its poor cost-effectiveness, adhesiolysis cannot be used as the first line of treatment. FBSS patients often suffer from chronic pain; accordingly, they become frustrated when this treatment produces a poor response. Therefore, before the procedure, the target group must be selected carefully. We sought to identify the pre-procedure factors predicting the effect of adhesiolysis in FBSS. A total of 150 patients were evaluated and analyzed retrospectively. Of these 150 patients, 69 were classified as responders three months after the procedure (46%). The outer diameter of the catheter during the procedure and grade of foraminal stenosis were correlated with the procedure effect. In conclusion, of the 2.1 mm diameter of the catheter, 1.7 mm of it was used during the procedure, and the milder the foraminal stenosis, the greater the pain reduction effect was three months after the procedure.

Loss of desmoglein-2 promotes gallbladder carcinoma progression and resistance to EGFR-targeted therapy through Src kinase activation.

Gallbladder carcinoma (GBC) exhibits poor prognosis due to local recurrence, metastasis, and resistance to targeted therapies. Using clinicopathological analyses of GBC patients along with molecular in vitro and tumor in vivo analysis of GBC cells, we showed that reduction of Dsg2 expression was highly associated with higher T stage, more perineural, and lymphatic invasion. Dsg2-depleted GBC cells exhibited significantly enhanced proliferation, migration, and invasiveness in vitro and tumor growth and metastasis in vivo through Src-mediated signaling activation. Interestingly, Dsg2 binding inhibited Src activation, whereas its loss activated cSrc-mediated EGFR plasma membrane clearance and cytoplasmic localization, which was associated with acquired EGFR-targeted therapy resistance and decreased overall survival. Inhibition of Src activity by dasatinib enhanced therapeutic response to anti-EGFR therapy. Dsg2 status can help stratify predicted patient response to anti-EGFR therapy and Src inhibition could be a promising strategy to improve the clinical efficacy of EGFR-targeted therapy.

Continuous suprascapular nerve block compared with single-shot interscalene brachial plexus block for pain control after arthroscopic rotator cuff repair.

OBJECTIVES: We compared the analgesic efficacy of a continuous suprascapular nerve block (C-SSNB) and a single-shot interscalene brachial plexus block (S-ISNB) for postoperative pain management in patients undergoing arthroscopic rotator cuff repair. METHODS: A total of 118 patients undergoing arthroscopic rotator cuff repair were randomly allocated to the S-ISNB or C-SSNB groups. Postoperative pain was assessed using the visual analog scale (VAS) at 1, 2, 6, 12, and 24 h postoperatively. Supplemental analgesic use was recorded as total equianalgesic fentanyl consumption. RESULTS: The C-SSNB group showed significantly higher VAS scores at 0-1 h and 1-2 h after the surgery than the S-ISNB group (4.9±2.2 versus 2.3±2.2; p<0.0001 and 4.8±2.1 versus 2.4±2.3; p<0.0001, respectively). The C-SSNB group showed significantly lower VAS scores at 6-12 h after the surgery than the S-ISNB group (4.1±1.8 versus. 5.0±2.5; p=0.031). The C-SSNB group required significantly higher doses of total equianalgesic fentanyl in the post-anesthesia care unit than the S-ISNB group (53.66±44.95 versus 5.93±18.25; p<0.0001). Total equianalgesic fentanyl in the ward and total equianalgesic fentanyl throughout the hospital period were similar between the groups (145.99±152.60 versus 206.13±178.79; p=0.052 and 199.72±165.50 versus 212.15±180.09; p=0.697, respectively). CONCLUSION: C-SSNB was more effective than S-ISNB at 6-12 h after the surgery for postoperative analgesia after arthroscopic rotator cuff repair.

Continuous suprascapular nerve block compared with single-shot interscalene brachial plexus block for pain control after arthroscopic rotator cuff repair

OBJECTIVES: We compared the analgesic efficacy of a continuous suprascapular nerve block (C-SSNB) and a single-shot interscalene brachial plexus block (S-ISNB) for postoperative pain management in patients undergoing arthroscopic rotator cuff repair. METHODS: A total of 118 patients undergoing arthroscopic rotator cuff repair were randomly allocated to the S-ISNB or C-SSNB groups. Postoperative pain was assessed using the visual analog scale (VAS) at 1, 2, 6, 12, and 24 h postoperatively. Supplemental analgesic use was recorded as total equianalgesic fentanyl consumption. RESULTS: The C-SSNB group showed significantly higher VAS scores at 0−1 h and 1−2 h after the surgery than the S-ISNB group (4.9±2.2 versus 2.3±2.2; p<0.0001 and 4.8±2.1 versus 2.4±2.3; p<0.0001, respectively). The C-SSNB group showed significantly lower VAS scores at 6−12 h after the surgery than the S-ISNB group (4.1±1.8 versus. 5.0±2.5; p=0.031). The C-SSNB group required significantly higher doses of total equianalgesic fentanyl in the post-anesthesia care unit than the S-ISNB group (53.66±44.95 versus 5.93±18.25; p<0.0001). Total equianalgesic fentanyl in the ward and total equianalgesic fentanyl throughout the hospital period were similar between the groups (145.99±152.60 versus 206.13±178.79; p=0.052 and 199.72±165.50 versus 212.15±180.09; p=0.697, respectively) CONCLUSION: C-SSNB was more effective than S-ISNB at 6−12 h after the surgery for postoperative analgesia after arthroscopic rotator cuff repair.

CXCR7 promotes migration and invasion in head and neck squamous cell carcinoma by upregulating TGF-ß1/Smad2/3 signaling.

The chemokine receptor CXCR7 has been suggested to play important roles in the progression of several types of cancers. However, few studies have investigated the biological roles of CXCR7 in head and neck squamous cell carcinoma (HNSCC). CXCR7 expression and its clinical implications were examined in 103 HNSCC tissues using immunohistochemistry (IHC). The biological roles and mechanisms of CXCR7-mediated signaling pathways were investigated in HNSCC cells through CXCR7 overexpression in vitro and in vivo. High expression of CXCR7 was significantly associated with tumor size (P = 0.007), lymph node metastasis (P = 0.004), and stage (P = 0.020) in HNSCC. Overexpression of CXCR7 in HNSCC cells enhanced cell migration and invasion in vitro and promoted lymph node metastasis in vivo. CXCR7 also induced epithelial-mesenchymal transition through PI3K/AKT. CXCR7 increased secretion of transforming growth factor-ß1 (TGF-ß1) and promoted EMT through phosphorylated Smad2/3. Taken together, our results provide functional and mechanistic roles of CXCR7 as a master regulator of oncogenic TGF-ß1/Smad2/3 signaling in HNSCC, suggesting that CXCR7 might be a therapeutic target for the treatment of HNSCC.

Decursin inhibits tumor growth, migration, and invasion in gastric cancer by down-regulating CXCR7 expression.

CXC chemokine receptor 7 (CXCR7) is highly expressed in various type of cancers and promotes cancer progression and metastasis. However, the biological role and regulation of CXCR7 in gastric cancer remains unclear, and little is known about compounds that modulate CXCR7. Here, we investigated the role of CXCR7 in gastric tumorigenesis, and the effects of decursin, which is derived from Angelica gigas Nakai, on CXCR7. Our results showed that CXCR7 significantly promoted growth of gastric cancer cells and increased migration and invasion, which was mediated by the STAT3/c-Myc pathway. We also confirmed that decursin had an antitumor effect through down-regulating the expression of CXCR7 in gastric cancer. Furthermore, apoptotic cell death was induced through the reduction of anti-apoptotic factors such as Bcl-2 in vitro and in vivo. Our findings show that CXCR7 in gastric cancer promotes cancer progression through the STAT3/c-Myc pathway and that decursin is a natural compound that may target CXCR7 in gastric cancer treatment.