Energy stress promotes P-bodies formation via lysine-63-linked polyubiquitination of HAX1.

Energy stress, characterized by the reduction of intracellular ATP, has been implicated in various diseases, including cancer. Here, we show that energy stress promotes the formation of P-bodies in a ubiquitin-dependent manner. Upon ATP depletion, the E3 ubiquitin ligase TRIM23 catalyzes lysine-63 (K63)-linked polyubiquitination of HCLS1-associated protein X-1 (HAX1). HAX1 ubiquitination triggers its liquid‒liquid phase separation (LLPS) and contributes to P-bodies assembly induced by energy stress. Ubiquitinated HAX1 also interacts with the essential P-body proteins, DDX6 and LSM14A, promoting their condensation. Moreover, we find that this TRIM23/HAX1 pathway is critical for the inhibition of global protein synthesis under energy stress conditions. Furthermore, high HAX1 ubiquitination, and increased cytoplasmic localization of TRIM23 along with elevated HAX1 levels, promotes colorectal cancer (CRC)-cell proliferation and correlates with poor prognosis in CRC patients. Our data not only elucidate a ubiquitination-dependent LLPS mechanism in RNP granules induced by energy stress but also propose a promising target for CRC therapy.

Prospects of molecular hydrogen in cancer prevention and treatment.

Gas signaling molecules, including carbon monoxide (CO), nitric oxide (NO), and hydrogen sulfide (H2S), have been shown to have cancer therapeutic potential, pointing to a new direction for cancer treatment. In recent years, a series of studies have confirmed that hydrogen (H2), a weakly reductive gas, also has therapeutic effects on various cancers and can mitigate oxidative stress caused by radiation and chemotherapy, reducing tissue damage and immunosuppression to improve prognosis. Meanwhile, H2 also has immunomodulatory effects, inhibiting T cell exhaustion and enhancing T cell anti-tumor function. It is worth noting that human intestinal flora can produce large amounts of H2 daily, which becomes a natural barrier to maintaining the body's resistance to diseases such as tumors. Although the potential anti-tumor mechanisms of H2 are still to be investigated, previous studies have shown that H2 can selectively scavenge highly toxic reactive oxygen species (ROS) and inhibit various ROS-dependent signaling pathways in cancer cells, thus inhibiting cancer cell proliferation and metastasis. The ROS scavenging ability of H2 may also be the underlying mechanism of its immunomodulatory function. In this paper, we review the significance of H2 produced by intestinal flora on the immune homeostasis of the body, the role of H2 in cancer therapy and the underlying mechanisms, and the specific application of H2 to provide new ideas for the comprehensive treatment of cancer patients.

Targeting NEDD8 suppresses surgical stress-facilitated metastasis of colon cancer via restraining regulatory T cells.

Regulatory T cells (Tregs) are a key determinant for the immunosuppressive and premetastatic niche for cancer progression after surgery resection. However, the precise mechanisms regulating Tregs function during surgical stress-facilitated cancer metastasis remain unknown. This study aims to unravel the mechanisms and explore potential strategies for preventing surgical stress-induced metastasis by targeting NEDD8. Using a surgical stress mouse model, we found that surgical stress results in the increased expression of NEDD8 in Tregs. NEDD8 depletion abrogates postoperative lung metastasis of colon cancer cells by inhibiting Treg immunosuppression and thereby partially recovering CD8+T cell and NK cell-mediated anti-tumor immunity. Furthermore, Treg mitophagy and mitochondrial respiration exacerbated in surgically stressed mice were attenuated by NEDD8 depletion. Our observations suggest that cancer progression may result from surgery-induced enhancement of NEDD8 expression and the subsequent immunosuppressive function of Tregs. More importantly, depleting or inhibiting NEDD8 can be an efficient strategy to reduce cancer metastasis after surgery resection by regulating the function of Tregs.

Pyroptosis in septic lung injury: Interactions with other types of cell death.

Sepsis is a life-threatening systemic inflammatory response syndrome caused by the host imbalanced response to infection. Lung injury is the most common complication of sepsis and one of the leading causes of patient death. Pyroptosis is a specific programmed cell death characterized by the release of inflammatory cytokines. Appropriate pyroptosis can reduce tissue damage and exert a protective effect against infection during sepsis. However, overactivated pyroptosis results in massive cell death, leading to septic shock, multiple organ dysfunction syndrome, and even an increased risk of secondary infection. Recent studies suggest that pyroptosis can interact with and cross-regulate other types of cell death programs to establish a complex network of cell death, which participates in the occurrence and development of septic lung injury. This review will focus on the interactions between pyroptosis and other types of cell death, including apoptosis, necroptosis, PANoptosis, NETosis, autophagy, and ferroptosis, to summarize the role of pyroptosis in sepsis-induced lung injury, and will discuss the potential therapeutic strategies of targeting pyroptosis during sepsis treatment.

Fasting-Mimicking Diet Drives Antitumor Immunity against Colorectal Cancer by Reducing IgA-Producing Cells.

As a safe, feasible, and inexpensive dietary intervention, fasting-mimicking diet (FMD) exhibits excellent antitumor efficacy by regulating metabolism and boosting antitumor immunity. A better understanding of the specific mechanisms underlying the immunoregulatory functions of FMD could help improve and expand the clinical application of FMD-mediated immunotherapeutic strategies. In this study, we aimed to elucidate the role of metabolic reprogramming induced by FMD in activation of antitumor immunity against colorectal cancer. Single-cell RNA sequencing analysis of intratumoral immune cells revealed that tumor-infiltrating IgA+ B cells were significantly reduced by FMD treatment, leading to the activation of antitumor immunity and tumor regression in murine colorectal cancer models. Mechanistically, FMD delayed tumor growth by repressing B-cell class switching to IgA. Therefore, FMD-induced reduction of IgA+ B cells overcame the suppression of CD8+ T cells. The immunoregulatory and antitumor effects of FMD intervention were reversed by IgA+ B-cell transfer. Moreover, FMD boosted fatty acid oxidation (FAO) to trigger RUNX3 acetylation, thus inactivating Cα gene transcription and IgA class switching. IgA+ B-cell expansion was also impeded in patients placed on FMD, while B-cell expression of carnitine palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme of FAO, was increased. Furthermore, CPT1A expression was negatively correlated with both IgA+ B cells and IgA secretion within colorectal cancer. Together, these results highlight that FMD holds great promise for treating colorectal cancer. Furthermore, the degree of IgA+ B cell infiltration and FAO-associated metabolic status are potential biomarkers for evaluating FMD efficacy. SIGNIFICANCE: Metabolic reprogramming of B cells induced by fasting-mimicking diet suppresses IgA class switching and production to activate antitumor immunity and inhibit tumor growth. See related commentary by Bush and Perry, p. 3493.

MTDCNet: A 3D multi-threading dilated convolutional network for brain tumor automatic segmentation.

Glioma is one of the most threatening tumors and the survival rate of the infected patient is low. The automatic segmentation of the tumors by reliable algorithms can reduce diagnosis time. In this paper, a novel 3D multi-threading dilated convolutional network (MTDC-Net) is proposed for the automatic brain tumor segmentation. First of all, a multi-threading dilated convolution (MTDC) strategy is introduced in the encoder part, so that the low dimensional structural features can be extracted and integrated better. At the same time, the pyramid matrix fusion (PMF) algorithm is used to integrate the characteristic structural information better. Secondly, in order to make the better use of context semantical information, this paper proposed a spatial pyramid convolution (SPC) operation. By using convolution with different kernel sizes, the model can aggregate more semantic information. Finally, the multi-threading adaptive pooling up-sampling (MTAU) strategy is used to increase the weight of semantic information, and improve the recognition ability of the model. And a pixel-based post-processing method is used to prevent the effects of error prediction. On the brain tumors segmentation challenge 2018 (BraTS2018) public validation dataset, the dice scores of MTDC-Net are 0.832, 0.892 and 0.809 for core, whole and enhanced of the tumor, respectively. On the BraTS2020 public validation dataset, the dice scores of MTDC-Net are 0.833, 0.896 and 0.797 for the core tumor, whole tumor and enhancing tumor, respectively. Mass numerical experiments show that MTDC-Net is a state-of-the-art network for automatic brain tumor segmentation.

Association of Mu-Opioid Receptor Expression With Long-Term Survival and Perineural Nerve Invasion in Patients Undergoing Surgery for Ovarian Cancer.

Background: Opioids are widely used during primary debulking surgery (PDS) for ovarian cancers, and a high mu-opioid receptor (MOR) expression predicts worse cancer outcomes. However, the impact of MOR expression on survival outcomes in ovarian cancers is still not clear. Methods: A retrospective cohort study was conducted in patients who underwent PDS in ovarian cancer patients. MOR expression was measured in tumor and normal tissue. Primary outcomes were overall survival (OS) and disease-free survival (DFS). Secondary outcomes included perineural invasion (PNI), intraoperative sufentanil consumption, length of stay (LOS), and verbal numerical rating scale (VNRS) on postoperative day 1 (POD1), POD3, and POD5. Results: After propensity score matching, a total of 366 patients were finally enrolled in this study. There were no significant differences in OS rates in patients with high versus low levels of MOR (1-year OS: 82.9% versus 83.3%, 3-year: 57.8% versus 59.1%, 5-year: 22.4% versus 23.1%,respectively) in the ovarian cancers. There were no significant differences in DFS between the groups. Intraoperative sufentanil consumption was higher in the MOR high-expression group compared with the MOR low-expression group. Tumors expressing high levels of MOR showed higher rates of PNI. VNRS in the MOR high-expression group was higher on POD1. Conclusion: MOR is not an independent predictor of worse survival in ovarian cancers but is associated with high rates of perineural invasion.

Intraoperative lidocaine infusion in patients undergoing pancreatectomy for pancreatic cancer: a mechanistic, multicentre randomised clinical trial.

BACKGROUND: Intravenous lidocaine has been postulated to improve long-term survival after surgery for pancreatic cancer through anti-inflammatory effects, anti-tumour effects, or both. We investigated whether intraoperative lidocaine improves survival after pancreatectomy for pancreatic cancer and whether lidocaine modified the formation of neutrophil extracellular traps (NETs), high levels of which are associated with poor prognosis. METHODS: Patients undergoing pancreatectomy were randomly assigned to i.v. lidocaine (continuous intraoperative infusion of 2 mg kg-1 h-1, after 1.5 mg kg-1 bolus at induction of anaesthesia) or saline placebo. The co-primary outcomes were survival/disease-free survival 3 yr after surgery. Secondary outcomes (masked to treatment allocation) included intraoperative opioid (sufentanil) dose, postoperative complications, and circulating and tumour-associated NETs (immunofluorescence assay, enzyme-linked immune assay, or both). RESULTS: A total of 563 participants (34.6% female; median age, 64 yr) completed 3 yr of clinical follow-up. Overall, 283 participants were randomised to lidocaine infusion, and 280 participants were randomised to placebo. Infusion of lidocaine did not alter overall (hazard ratio [HR]=0.98; 95% confidence interval [CI], 0.81-1.17; P=0.79) or disease-free survival (HR=0.91; 95% CI, 0.71-1.17; P=0.44). Mean intraoperative sufentanil dose was reduced by lidocaine infusion (47.6 µg [4.6]) compared with placebo (68.4 µg [4.8]; P<0.001), but postoperative complications and length of hospital stay were similar between groups. Circulating NETs were lower after lidocaine infusion up to 3 days after surgery, but tumour-associated NETs were not altered by intraoperative treatment. CONCLUSION: In patients undergoing pancreatectomy for pancreatic cancer, intraoperative infusion of lidocaine did not improve overall or disease-free survival. Reduced formation of circulating NETs was absent in pancreatic tumour tissue. CLINICAL TRIAL REGISTRATION: NCT03245346; updated in Chi-CTR-2000035469.

Surgical Stress and Cancer Progression: New Findings and Future Perspectives.

PURPOSE OF REVIEW: The stress response to surgery is essential for maintaining homeostasis and exhibits anti-tumor effects; however, an ongoing and exaggerated stress response may have adverse clinical consequences and even promote cancer progression. This review will discuss the complex relationship between surgical stress and cancer progression. RECENT FINDINGS: Surgical stress exhibits both anti-tumor and cancer-promoting effects by causing changes in the neuroendocrine, circulatory, and immune systems. Many studies have found that many mechanisms are involved in the process, and the corresponding targets could be applied for cancer therapy. Although surgical stress may have anti-tumor effects, it is necessary to inhibit an excessive stress response, mostly showing cancer-promoting effects.

Tissue Factor-Enriched Neutrophil Extracellular Traps Promote Immunothrombosis and Disease Progression in Sepsis-Induced Lung Injury.

Background: Patients with sepsis may progress to acute respiratory distress syndrome (ARDS). Evidence of neutrophil extracellular traps (NETs) in sepsis-induced lung injury has been reported. However, the role of circulating NETs in the progression and thrombotic tendency of sepsis-induced lung injury remains elusive. The aim of this study was to investigate the role of tissue factor-enriched NETs in the progression and immunothrombosis of sepsis-induced lung injury. Methods: Human blood samples and an animal model of sepsis-induced lung injury were used to detect and evaluate NET formation in ARDS patients. Immunofluorescence imaging, ELISA, Western blotting, and qPCR were performed to evaluate in vitro NET formation and tissue factor (TF) delivery ability. DNase, an anti-TF antibody, and thrombin inhibitors were applied to evaluate the contribution of thrombin to TF-enriched NET formation and the contribution of TF-enriched NETs to immunothrombosis in ARDS patients. Results: Significantly increased levels of TF-enriched NETs were observed in ARDS patients and mice. Blockade of NETs in ARDS mice alleviated disease progression, indicating a reduced lung wet/dry ratio and PaO2 level. In vitro data demonstrated that thrombin-activated platelets were responsible for increased NET formation and related TF exposure and subsequent immunothrombosis in ARDS patients. Conclusion: The interaction of thrombin-activated platelets with PMNs in ARDS patients results in local NET formation and delivery of active TF. The notion that NETs represent a mechanism by which PMNs release thrombogenic signals during thrombosis may offer novel therapeutic targets.

Targeting the mu-Opioid Receptor for Cancer Treatment.

PURPOSE OF REVIEW: Opioids are still the most effective and widely used treatments for acute and chronic pain in cancer patients. This review focuses on the impact of opioids and mu-opioid receptors (MOR) on tumor progression and providing new ideas for targeting the MOR in cancer treatment. RECENT FINDINGS: Studies estimated that opioids facilitate tumor progression and are related to the worse prognosis in cancer patients. As the primary receptor of opioids, MOR is involved in the regulation of malignant transformation of tumors and participating in proliferation, invasion, metastasis, and angiogenesis. MOR may be a new molecular marker of malignant tumors and thus become a new target for cancer therapy, which may be beneficial to the outcomes of cancer patients.

NBPF4 mitigates progression in colorectal cancer through the regulation of EZH2-associated ETFA.

Colorectal cancer (CRC) is one of the leading causes of death worldwide, and hence, there is a need to elucidate the molecular mechanisms contributing to the progression of CRC. In this study, we aimed at assessing the role of long non-coding RNA NBPF4 on the tumorigenesis of CRC. Silencing or overexpression experiments were performed on HCT116 and SW260 in vitro models. BALB/c athymic female nude mice aged 5-6 weeks were used as in vivo models. To assess the relationship between NBPF4 and its regulatory RNA pull-down assay, RNA immunoprecipitation, luciferase activity, Western blotting and qRT-PCR were employed. Initially, we identified that NBPF4 was downregulated in CRC tissues and cell lines. Furthermore, we observed that NBPF4 decreased tumorigenesis in both in vitro and in vivo models. Additionally, we identified that ETFA was highly expressed in CRCs and was negatively associated with NBPF4. Subsequently, we identified that EZH2, a transcriptional factor, activated ETFA by enhancing the methylation of its promoter, and EZH2 was also highly regulated in CRCs. Using COAD and READ databases, we confirmed that EZH2 and ETFA were positively correlated. Furthermore, we identified NBPF4 and EZH2 were targets for ZFP36, which bound and positively regulated NBPF4. This prevented NBPF4 from binding to its negative regulator miR-17-3p. Our results demonstrated that NBPF4 downregulated EZH2 and stabilized itself by binding to ZFP36, thus escaping from inhibition by miR-17-3p, which allowed mitigation of CRC through inhibition of ETFA.

Association of Mu-Opioid Receptor(MOR) Expression and Opioids Requirement With Survival in Patients With Stage I-III Pancreatic Ductal Adenocarcinoma.

BACKGROUND: The use of opioids in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) is associated with shorter survival and not dependent on the expression of the mu-opioid receptor (MOR). The role of opioid use and MOR expression in stage I-III PDAC has not been investigated. METHODS: We conducted retrospective study in patients with stage I-III PDAC. MOR expression and OPRM1 gene expression in tumour tissue and non-tumour tissue was measured. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Secondary endpoints included perineural invasion, intraoperative sufentanil consumption, and length of stay. We performed a subgroup group analysis to evaluate the interaction between levels of MOR expression, amount of opioids use (high versus low) and its association with survival. RESULTS: A total of 236 patients were enrolled in this study.There were no significantly difference in OS rates in patients with high versus low levels of MOR (1-year OS: 65.2% versus 70.6%, P=0.064; 3-year: 31.4% versus 35.8%, P=0.071; 5-year: 19.4% versus. 16.2%, P=0.153, respectively) in the tumours. The DFS rates between the groups were no significantly difference. Of note, a high expression of MOR combined with high opioid consumption was associated with poor prognosis in stage I-III PDAC patients. Tumor expressing high levels of MOR show higher rates of perineural invasion. CONCLUSION: MOR is not an independent predictor of poor survival in stage I-III PDAC but associated with perineural invasion. Patients requiring high amounts of opioids intraoperatively show worse outcome if they are expressing high levels of MOR.

GABAB receptor inhibits tumor progression and epithelial-mesenchymal transition via the regulation of Hippo/YAP1 pathway in colorectal cancer.

Gamma-Aminobutyric Acid Type B Receptor (GABABR) plays essential roles in tumor progression. However, the function of GABABR in colorectal cancer (CRC) needs further clarification. As the main part of GABABR, GABABR1 expression was identified significantly lower in tumor tissues than those in non-tumor normal tissues and that CRC patients with high GABABR1 expression lived longer. Further studies indicated that knockdown of GABABR1 elevated CRC cell proliferation, migration, and invasion. Furthermore, knockdown of GABABR1 activated the expression of the epithelial-mesenchymal transition (EMT)-related proteins N-cadherin and Vimentin, whereas decrease the protein level of E-cadherin. In addition, activation of Hippo/YAP1 signaling contributes to the GABABR1 down-regulation promoted proliferation, migration, invasion and EMT in CRC cells. At last, we verified the contribution of Hippo/YAP1 signaling in the GABABR1 down-regulation impaired biological phenotype of colon cancer cells in vivo. In summary, these data indicate that GABABR1 impairs the migration and invasion of CRC cells by inhibiting EMT and the Hippo/YAP1 pathway, suggesting that GABABR1 could be a potential therapeutic target for CRC.

The Role of Ferroptosis in Acute Respiratory Distress Syndrome.

Ferroptosis is a newly discovered type of regulated cell death that is different from apoptosis, necrosis and autophagy. Ferroptosis is characterized by iron-dependent lipid peroxidation, which induces cell death. Iron, lipid and amino acid metabolism is associated with ferroptosis. Ferroptosis is involved in the pathological development of various diseases, such as neurological diseases and cancer. Recent studies have shown that ferroptosis is also closely related to acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS), suggesting that it can be a novel therapeutic target. This article mainly introduces the metabolic mechanism related to ferroptosis and discusses its role in ALI/ARDS to provide new ideas for the treatment of these diseases.

International multicentre observational study to evaluate the association between perioperative red blood cell transfusions and 1-year mortality after major cancer surgery (ARCA-1): study design, statistical analysis plan and study protocol.

INTRODUCTION: Blood transfusion is still common in patients undergoing major cancer surgery. Blood transfusion can be associated with poor prognosis in patients with cancer. Perioperative Care in the Cancer Patient -1 (ARCA-1) aims to assess in a large cohort of patients the current incidence, pattern of practice and associations between perioperative blood transfusions and 1-year survival in patients undergoing major cancer surgery. METHODS AND ANALYSIS: ARCA-1 is a prospective international multicentre observational study that will include adult patients scheduled to have major cancer surgical procedures with the intention to cure, and an overnight planned hospital admission. The study will be opened for 1 year for enrolment (7 January 2020-7 February 2021). Each centre will enrol patients for 30 days. The primary endpoint of this study is all-cause mortality 1 year after major cancer surgery. Secondary endpoints are rate of perioperative blood product use, cancer-specific mortality at 1 year and PFSs and 30-day morbidity and mortality. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board at The University of Texas-MD Anderson Cancer Center. The study results will be published in peer-reviewed journals and disseminated at international conferences. TRIAL REGISTRATION NUMBER: NCT04491409.

Impact of anesthesia methods on perioperative systemic inflammation and long-term outcomes in patients undergoing surgery for hepatocellular carcinoma: a propensity score-matched analysis.

BACKGROUND: Recent studies have shown regional anesthesia might improve the survival of cancer patients. We hypothesized that general-epidural anesthesia (GEA) was associated with longer survival than general anesthesia (GA) in patients undergoing hepatocellular carcinoma (HCC) resections. METHODS: A retrospective study included patients who received curative resection for HCC between January 2014 to December 2017. Patients were grouped in GEA vs. GA. After propensity score matching, perioperative inflammatory scores were calculated. Grade of postoperative complications, length of stay (LOS), dosage of sufentanil used and times of patients requiring rescue analgesia in both groups were compared for intraoperative and postoperative parameter. Survival curves were constructed from the date of surgery to death, univariable and multivariable Cox regression models were used to compare hazard ratios for death. RESULTS: A total of 772 patients were included in the study. With 386 patients in GA group and 386 patients in GEA group. After propensity score matching, the demographic and baseline biomarkers in the two groups were similar. Patients in GEA group showed significantly lower inflammatory scores. Grade of postoperative complications, LOS, opioid use, and times of patients requiring rescue analgesia was significantly lower in the GEA group. The overall survival (OS) and disease-free survival (DFS) rate was significantly lower in the GA group (54.2% vs. 62.3%, 41.2% vs. 52.5%, P<0.001). The multivariate analysis indicated the GA was associated with shorter OS (HR: 1.28, 95% CI: 1.07-2.02, P<0.001) and DFS (HR: 1.06, 95% CI: 1.03-1.71, P<0.001). CONCLUSIONS: GA combined with epidural anesthesia is associated with lower levels of inflammation, and longer survival in patients undergoing hepatectomy.

Effects of Intravenous Infusion of Lidocaine on Short-Term Outcomes and Survival in Patients Undergoing Surgery for Ovarian Cancer: A Retrospective Propensity Score Matching Study.

BACKGROUND: Intravenous lidocaine has been shown to reduce opioid consumption and is associated with favourable outcomes after surgery. In this study, we explored whether intraoperative lidocaine reduces intraoperative opioid use and length of stay (LOS) and improves long-term survival after primary debulking surgery for ovarian cancer and explored the correlation between SCN9A expression and ovarian cancer prognosis. METHODS: This retrospective study included patients who underwent primary debulking surgery(PDS) for ovarian cancer from January 2015 to December 2018. The patients were divided into non-lidocaine and lidocaine [bolus injection of 1.5 mg/kg lidocaine at the induction of anaesthesia followed by a continuous infusion of 2 mg/(kg∙h) intraoperatively] groups. Intraoperative opioid consumption, the verbal numeric rating scale (VNRS) at rest and LOS were recorded. Propensity score matching was used to minimize bias, and disease-free survival (DFS) and overall survival (OS) were compared between the two groups. RESULTS: After propensity score matching(PSM), the demographics were not significantly different between the groups. The intraoperative sufentanil consumption in the lidocaine group was significantly lower than that in the non-lidocaine group (Mean: 35.6 µg vs. 43.2 µg, P=0.035). LOS was similar between the groups (12.0 days vs. 12.4 days, P=0.386). There was a significant difference in DFS between the groups (32.3% vs. 21.6%, P=0.015), and OS rates were significantly higher in the lidocaine group than in the non-lidocaine group (35.2% vs. 25.6%, P=0.042). Multivariate analysis indicated that intraoperative lidocaine infusion was associated with prolonged OS and DFS. CONCLUSION: Intraoperative intravenous lidocaine infusion appears to be associated with improved OS and DFS in patients undergoing primary debulking surgery for ovarian cancer. Our study has the limitations of a retrospective review. Hence, our results should be confirmed by a prospective randomized controlled trial.

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.

Increased mu-opioid receptor expression is associated with reduced disease-free and overall survival in laryngeal squamous cell carcinoma.

BACKGROUND: Expression of the mu-opioid receptor (MOR) is associated with poor long-term outcomes in various types of cancer. The association between MOR expression and clinical outcomes in laryngeal squamous cell carcinoma (LSCC) is not clear. METHODS: This retrospective study included patients who underwent laryngectomy for LSCC. The expression pattern of the MOR protein and OPRM1 gene in tumours and corresponding adjacent non-carcinoma specimens was measured. Propensity score matching was used to minimise bias. The primary endpoints were overall survival (OS) and disease-free survival (DFS). The secondary endpoints were intraoperative sufentanil consumption, grade of surgical complications according to the Clavien-Dindo classification, and hospital length of stay. RESULTS: A total of 207 LSCC patients were enrolled. After propensity score matching, there was a significant difference in DFS between groups at 1, 3, and 5 yr (60.2% vs 81.2%, P=0.019; 39.4% vs 50.2%, P=0.026; 37.5% vs 42.5%, P=0.023, respectively) in patients with high MOR expression. The OS rates at 1, 3, and 5 yr were significantly lower in the high MOR expression group (81.2% vs 93.2%, P=0.027; 57.7% vs 78.3%, P<0.001; 42.5% vs 60.3%, P<0.001, respectively). The multivariate analysis indicated that high MOR expression was associated with worse DFS and OS (hazard ratio: 1.52, 95% confidence interval: 1.07, 2.25, P=0.034; hazard ratio: 1.42, 95% confidence interval: 1.17, 2.34, P=0.032). CONCLUSION: High MOR expression may be associated with poor prognosis in patients with LSCC, suggesting that MOR could be used as a valuable molecular biomarker to predict prognosis of LSCC patients.