Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer.

Morphine, a mu-opioid receptor (MOR) agonist, has been extensively used to treat advanced cancer pain. In particular, in patients with cancer metastasis, both morphine and anticancer drugs are given simultaneously. However, evidence showed that morphine might be a risk factor in promoting the tumor's malignant potential. In this study, we report that treatment with morphine could activate MOR and lead to the promotion of proliferation, migration, and invasion in HCT116 and DLD1 colorectal cancer (CRC) cells with time-concentration dependence. Moreover, morphine can also contribute to cetuximab's drug resistance, a targeted drug widely used to treat advanced CRC by inducing the activation of epidermal growth factor receptor (EGFR). The cell phenotype includes proliferation, migration, invasion, and drug resistance, which may be reversed by MOR knockdown or adding nalmefene, the MOR receptor antagonist. Receptor tyrosine kinase array analysis revealed that morphine selectively induced the transactivation of EGFR. EGFR transactivation resulted in the activation of ERK1/2 and AKT. In conclusion, morphine induces the transactivation of EGFR via MOR. It activates the downstream signal pathway AKT-MTOR and RAS-MAPK, increases proliferation, migration, and invasion, and promotes resistance to EGFR inhibitors in a CRC cell line. Furthermore, we verified that EGFR inhibition by cetuximab strongly reversed the protumoral effects of morphine in vitro and in vivo. Collectively, we provide evidence that morphine-EGFR signaling might be a promising therapeutic target for CRC patients, especially for cetuximab-resistant CRC patients.

Tailored duration of adjuvant trastuzumab for human epidermal growth factor receptor 2-positive breast cancer.

We assumed that the effect of adjuvant trastuzumab on survival is mediated by the treatment time and we conducted this trial-level meta-regression to determine the appropriate length of treatment. Twelve adjuvant trastuzumab trials (from January 2000 to June 2019, consisting of 20,271 patients) were included. We considered 12-month trastuzumab treatment as the standard. The primary study endpoint was disease-free survival (DFS). By quantifying the relationship between shortened treatment time (month) and altered recurrence risk (expressed as hazard ratio), we found the regression coefficient ß was 0.05 (95% confidence interval: 0.02-0.08, P = 0.002), indicating the recurrence risk would increase 5.1% for each month that treatment was shortened. Accordingly, 3, 6, and 9-month reductions in treatment time resulted in 16%, 35%, and 57% increases in recurrence risk, respectively. We revealed a significant linear association between shortened treatment time of trastuzumab and recurrence risk. The clinical duration of adjuvant trastuzumab should be tailored.

Dezocine regulates the malignant potential and aerobic glycolysis of liver cancer targeting Akt1/GSK-3ß pathway.

BACKGROUND: Due to the "ceiling effect" of respiratory depression and the non-addictiveness, the consumption of dezocine is increasing quickly in the cancer surgery perioperative period for security and comfort reasons in China. Former studies find dezocine inhibits the norepinephrine transporters (NET) and serotonin transporters (SERT) and sigma-1opioid receptors. Given the complexity of the molecular mechanism, the effect of dezocine on tumor cells need to be studied. In this study, we investigated the effect of dezocine on HepG2 and Hep 3B liver cancer cell lines growth and glycolysis, and the molecular mechanisms behind. METHODS: HepG2 and Hep 3B cells viability and migration were measured by CCK8, Wound healing and transwell assay, Extracellular acidification rate (ECAR) was used to index the aerobic glycolysis of liver cancer cells and western blot analysis showed protein expression levels in the cells. SC79, an agonist of Akt, and the siRNA silence of Akt1 aimed to regulate Akt1 activity and expression in the reverse experiments. RESULTS: Dezocine played opposite roles in HepG2 and Hep 3B cells viability and migration in a concentration-dependent manner (P<0.01). Dezocine has diverse effects on aerobic glycolysis and adjusts the serine/threonine kinase 1 (Akt1)-glycogen synthase kinase-3ß (GSK-3ß) pathway. The effects of SC79 and the siRNA silence of Akt1 could reverse the effects of dezocine on HepG2 and Hep 3B cells. CONCLUSIONS: As an analgesic drug widely used in clinical practice, dezocine play reversed roles on HepG2 and Hep 3B cells viability and migration targeting Akt1/GSK-3ß pathway then the glycolysis in a concentration-dependent manner.

Fasting inhibits aerobic glycolysis and proliferation in colorectal cancer via the Fdft1-mediated AKT/mTOR/HIF1α pathway suppression.

Evidence suggests that fasting exerts extensive antitumor effects in various cancers, including colorectal cancer (CRC). However, the mechanism behind this response is unclear. We investigate the effect of fasting on glucose metabolism and malignancy in CRC. We find that fasting upregulates the expression of a cholesterogenic gene, Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1), during the inhibition of CRC cell aerobic glycolysis and proliferation. In addition, the downregulation of FDFT1 is correlated with malignant progression and poor prognosis in CRC. Moreover, FDFT1 acts as a critical tumor suppressor in CRC. Mechanistically, FDFT1 performs its tumor-inhibitory function by negatively regulating AKT/mTOR/HIF1α signaling. Furthermore, mTOR inhibitor can synergize with fasting in inhibiting the proliferation of CRC. These results indicate that FDFT1 is a key downstream target of the fasting response and may be involved in CRC cell glucose metabolism. Our results suggest therapeutic implications in CRC and potential crosstalk between a cholesterogenic gene and glycolysis.

miR-124/VAMP3 is a novel therapeutic target for mitigation of surgical trauma-induced microglial activation.

Activation of microglia and the subsequently elevated inflammatory cytokine release in the brain during surgery predispose individuals to cognitive dysfunction, also known as postoperative cognitive dysfunction (POCD). miR-124 is one of the most abundant microRNAs in the brain that regulates microglial function. Elucidating the role of miR-124 in microglial activation in the context of surgery may therefore promote understanding of as well as therapeutic development for post-surgical disorders involving microglial activation. The downstream targets of miR-124 were investigated using bioinformatic screening and dual-luciferase reporter assay validation, and vesicle-associated membrane protein 3 (VAMP3) was identified as a potential target. The kinetics of miR-124/VAMP3 expression was first examined in vitro in microglial cells (primary microglia and BV2 microglial cells) following lipopolysaccharide (LPS) stimulation. LPS induced a time-dependent decrease of miR-124 and upregulated the expression of VAMP3. Manipulating miR-124/VAMP3 expression by using miR-124 mimics or VAMP3-specific siRNA in LPS-stimulated BV2 microglial cells inhibited BV2 microglial activation-associated inflammatory cytokine release. To further examine the role of miR-124/VAMP3 in a surgical setting, we employed a rat surgical trauma model. Significant microglial activation and altered miR-124/VAMP3 expression were observed following surgical trauma. We also altered miR-124/VAMP3 expression in the rat surgical trauma model by administration of exogenous miR-124 and by using electroacupuncture, which is a clinically applicable treatment that modulates microglial function and minimizes postoperative disorders. We determined that electroacupuncture treatment specifically increases the expression of miR-124 in the hypothalamus and hippocampus. Increased miR-124 expression with a concomitant decrease in VAMP3 expression resulted in decreased inflammatory cytokine release related to microglial activation post-surgery. Our study indicates that miR-124/VAMP3 is involved in surgery-induced microglial activation and that targeting miR-124/VAMP3 could be a potential therapeutic strategy for postoperative disorders involving microglial activation.

High Glucose Stimulates Expression of MFHAS1 to Mitigate Inflammation via Akt/HO-1 Pathway in Human Umbilical Vein Endothelial Cells.

Hyperglycemia is a highly dangerous factor to various diseases, even resulting in death of people. Inflammation plays a key role in this process. The aim of this study was to explore the role of malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) in high-glucose induced inflammation. Our research showed that high glucose stimulated the expression of MFHAS1, and overexpression of MFHAS1 can attenuate high-glucose induced inflammation in endothelial cells by decreasing the secretion of cytokines interleukin-1ß (IL-1ß), interleukin-1α (IL-1α), adhesion molecule intercellular adhesion molecule-1 (ICAM), interleukin-6 (IL-6), interleukin-8 (IL-8), and chemokine ligand 1 (CXCL-1). Furthermore, we found that MFHAS1 promoted the phosphorylation of Akt and the expression of heme oxygenase-1 (HO-1). Our results indicated that MFHAS1 deadened high-glucose induced inflammation by activating AKT/HO-1 pathway, suggesting that MFHAS1 may act as a new therapeutic target of diabetes mellitus.

General anesthesia combined with epidural anesthesia ameliorates the effect of fast-track surgery by mitigating immunosuppression and facilitating intestinal functional recovery in colon cancer patients.

PURPOSE: The purpose of this study is to investigate the influence of anesthetic methods on markers of anti-tumor immunity and intestinal functions in fast-track surgery in colon cancer (CC) patients during the perioperative period. PATIENTS AND METHODS: A total of 53 patients with American Society of Anesthesiologists (ASA) I-II status randomly received general anesthesia (G group, n = 27) or general anesthesia combined with epidural anesthesia (E group, n = 26) for surgical tumor resection. The recovery times of intestinal function were evaluated in both groups postoperatively. The frequencies of different subsets of CD4+ T cells and myeloid-derived suppressor cells and C-reactive protein (CRP) were measured by flow cytometry and enzyme-linked immunosorbent assay, respectively, before anesthesia (t0), 1 h after the beginning of surgery (t1), 1 h after the end of surgery (t2), and on day 2 (t3) and day 5 (t4) post-surgery. RESULTS: There was no significant difference in demographic characteristics between the two groups, but the E group of patients received significantly lower amounts of morphine and sevoflurane. In comparison with those in the G group, significantly greater numbers of lymphocytes and elevated frequencies of Th1 cells were detected at t3 and t4 post-surgery in the E group (p < 0.01). Significantly lower percentages of Th2 cells and regulatory T cells were detected in the E group at t2-4 post-surgery. Whereas the levels of plasma CRP increased post-surgery in both groups, the levels of CRP were significantly lower in the E group than those in the G group at t3-4 post-surgery (p < 0.05). The times to the first flatus and to tolerate a full diet were significantly shorter in the E group than those in the G group (p < 0.01). CONCLUSION: General anesthesia combined with epidural anesthesia plays an important role in fast-track surgery, mitigating the surgical stress-related impairment of anti-tumor immune responses and hastening the recovery of intestinal function. This combination might also help to improve long-term outcomes for CC patients.

The effect of anesthetic technique on survival in human cancers: a meta-analysis of retrospective and prospective studies.

Animal models have shown that regional anesthesia (combined with or without general anesthesia) would attenuate the surgical stress response by preserving immune function and result in better long-term outcome. In order to test the hypothesis that cancer patients who had surgery with epidural anesthesia (EA) would have better outcome (either overall survival [OS] or recurrence-free survival [RFS]) than those who were general anesthesia (GA), we performed this meta-analysis. By searching relevant literature, a total of 14 studies containing 18 sub-studies (seven in OS analysis and eleven in RFS analysis) were identified and meta-analyzed. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the strength of association. For OS, the random-effects model was used to analyze the data and demonstrated an OS benefit in favor of EA compared with GA alone (HR = 0.84, 95% CI 0.74-0.96, P = 0.013). The influence analysis showed the robustness of the results. Specifically, a significantly positive association between EA and improved OS was observed in colorectal cancer (HR = 0.65, 95% CI 0.43-0.99, P = 0.045). For RFS, the random-effects model was used to analyze the data and no significant relationship between RFS benefit and EA (HR = 0.88, 95% CI 0.64-1.22, P = 0.457) was detected. In conclusion, our meta-analysis suggests that epidural anesthesia and/or analgesia might be associated with improved overall survival in patients with operable cancer undergoing surgery (especially in colorectal cancer), but it does not support an association between epidural anesthesia and cancer control. Prospective studies are needed to determine whether the association between epidural use and survival is causative.