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

Lü, Hong; Zhang, Hao; Weng, Mei lin; Zhang, Jin; Jiang, Nan; Cata, Juan P.; Ma, Duan; Chen, Wan Kun; Miao, Chang Hong

doi:10.1002/jcp.30161

Cited by 29 publications

(18 citation statements)

References 43 publications

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“…A number of MOR agonists, such as morphine, have been reported to be effective in alleviating severe pain; however, there were obvious limitations, such as they are prone to abuse, which is associated with an increased, risk of overdose, and serious side effects ( 30 ). In addition, several studies on morphine have shown that it promotes the proliferation, apoptosis, migration, and invasion in the breast ( 22 , 31 ), lung ( 6 , 32 , 33 ) and colorectal cancer cell lines ( 34 ), and a few studies indicated that morphine has an anti-tumor effect ( 35 , 36 ). Its potential mechanisms include the promotion of tumor angiogenesis, cell cycle arrest, and apoptosis of cancer cells ( 22 , 34 , 36 ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, several studies on morphine have shown that it promotes the proliferation, apoptosis, migration, and invasion in the breast ( 22 , 31 ), lung ( 6 , 32 , 33 ) and colorectal cancer cell lines ( 34 ), and a few studies indicated that morphine has an anti-tumor effect ( 35 , 36 ). Its potential mechanisms include the promotion of tumor angiogenesis, cell cycle arrest, and apoptosis of cancer cells ( 22 , 34 , 36 ). Agonists for the KOR, such as nalbuphine, have been shown to provide similar analgesic effects comparable to morphine, suppressing various acute or chronic pain and cancer pain effectively, and reducing morphine-related side effects such as respiratory depression, addiction ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

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Agonists Specific for κ-Opioid Receptor Induces Apoptosis of HCC Cells Through Enhanced Endoplasmic Reticulum Stress

Tan¹,

Wang²,

Cheng³

et al. 2022

Front. Oncol.

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Cancer pain is an important factor affecting life quality of patients especially in the advanced stage and relieving pain is one of fundamental strategies for cancer treatment. Opioids such as morphine are the most widely used in clinics. However, they have been reported to be associated with the occurrence and development of several types of cancer. Thus, search for an opioid that has analgesic effect and can retard cancer progress simultaneously is critical for cancer management. In this study, we first examined the expression of μ and κ (MOR and KOR) in cell lines and tumor tissues of hepatocellular carcinoma (HCC), a malignant tumor with high mortality, and then compared the effects of opioid receptors-specific agonists on malignant phenotypes of HCC cells in vitro and tumor growth in an HCC xenograft mouse model. KOR and MOR were found to be highly expressed in HCC cell lines and HCC tissues. The KOR-specific agonist U50488h, oxycodone (agonist for both KOR and MOR) and the MOR-specific agonist morphine inhibited HCC cell proliferation, while only U50488h and oxycodone suppressed colony formation and migration of HCC cells. U50488h and oxycodone, but not morphine, induced HCC apoptosis. Further detection of PERK, GRP78 and CHOP revealed that PERK signaling was upregulated by treatment with U50488h, while treatment with the PERK inhibitor GSK2656157 partially reversed the promotion of apoptosis and inhibition of cell proliferation by U50488h, indicating that endoplasmic reticulum stress is associated with its suppressing effect on HCC malignant phenotypes. Similar to the in vitro results, HCC growth was significantly reduced by administration of U50488h and oxycodone, but not by morphine, in the HCC xenograft mouse model. PERK and caspase-3 in the HCC tissues were up-regulated by U50488h treatment as detected by immunohistochemistry and western blotting. Taken together, our results revealed that activation of KOR by U50488h inhibited malignant phenotypes of HCC both in vitro and in vivo, while activation of MOR by morphine did not have such effect. Because of their dual roles in the relief of pain and in the suppression of malignant phenotypes, opioids such as U50488h that act on KOR should be considered as the first choice for HCC management.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Agonists Specific for κ-Opioid Receptor Induces Apoptosis of HCC Cells Through Enhanced Endoplasmic Reticulum Stress

Tan¹,

Wang²,

Cheng³

et al. 2022

Front. Oncol.

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“…This analysis indicated that six pathways were significantly enriched in the high-risk group, including axon guidance, GnRH signaling, MAPK signaling, melanogenesis, vascular smooth muscle contraction, and VEGF signaling pathways. All six of these pathways have been associated with poor prognosis for CRC ( Je et al, 2013 ; Zhu et al, 2013 ; Hohla et al, 2014 ; Sun et al, 2018 ; Lu et al, 2020 ; Zhao et al, 2020a ), which may provide insight into the molecular mechanisms underlying poor prognosis in the high-risk group.…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of a Six Immune-Related Genes Signature for Predicting Prognosis in Patients With Stage II Colorectal Cancer

Xie

Yin

et al. 2021

Front. Genet.

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BackgroundImmune-related genes (IRGs) play important roles in the tumor immune microenvironment and can affect the prognosis of cancer. This study aimed to construct a novel IRG signature for prognostic evaluation of stage II colorectal cancer (CRC).MethodsGene expression profiles and clinical data for stage II CRC patients were collected from the Cancer Genome Atlas and Gene Expression Omnibus database. Univariate, multivariate Cox regression, and least absolute shrinkage and selection operator regression were used to develop the IRG signature, namely IRGCRCII. A nomogram was constructed, and the “Cell Type Identification by Estimating Relative Subsets of RNA Transcripts” (CIBERSORT) method was used to estimate immune cell infiltration. The expression levels of genes and proteins were validated by qRT-PCR and immunohistochemistry in 30 pairs of primary stage II CRC and matched normal tissues.ResultsA total of 466 patients with stage II CRC were included, and 274 differentially expressed IRGs were identified. Six differentially expressed IRGs were detected and used to construct the IRGCRCII signature, which could significantly stratify patients into high-risk and low-risk groups in terms of disease-free survival in three cohorts: training, test, and external validation (GSE39582). Receiver operating characteristics analysis revealed that the area under the curves of the IRGCRCII signature were significantly greater than those of the OncotypeDX colon signature at 1 (0.759 vs. 0.623), 3 (0.875 vs. 0.629), and 5 years (0.906 vs. 0.698) disease-free survival, respectively. The nomogram performed well in the concordance index (0.779) and calibration curves. The high-risk group had a significantly higher percentage of infiltrated immune cells (e.g., M2 macrophages, plasma cells, resting mast cells) than the low-risk group. Finally, the results of qRT-PCR and immunohistochemistry experiments performed on 30 pairs of clinical specimens were consistent with bioinformatics analysis.ConclusionThis study developed and validated a novel immune prognostic signature based on six differentially expressed IRGs for predicting disease-free survival and immune status in patients with stage II CRC, which may reflect immune dysregulation in the tumor immune microenvironment.

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“…Deregulation of Thyroid Hormones (THs) system in Colorectal Cancer (CRC) suggests that these hormones may play roles in CRC pathogenesis [ 47 ]. Morphine promotes tumorigenesis and cetuximab resistance via EGFR signaling activation in human colorectal cancer [ 48 ]. Glycolysis and glycine, serine and threonine were activated in CRC, and these alterations may promote cell proliferation [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing of rectal cancer identifies locally recurrent mutations in the Wnt pathway

Yang

et al. 2021

Aging

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Locally recurrent rectal cancer (LRRC) leads to a poor prognosis and appears as a clinically predominant pattern of failure. In this research, whole-exome sequencing (WES) was performed on 21 samples from 8 patients to search for the molecular mechanisms of LRRC. The data was analyzed by bioinformatics. Gene Expression Profiling Interactive Analysis (GEPIA) and Human Protein Atlas (HPA) were performed to validate the candidate genes. Immunohistochemistry was used to detect the protein expression of LEF1 and CyclinD1 in LRRC, primary rectal cancer (PRC), and non-recurrent rectal cancer (NRRC) specimens. The results showed that LRRC, PRC, and NRRC had 668, 794, and 190 specific genes, respectively. FGFR1 and MYC have copy number variants (CNVs) in PRC and LRRC, respectively. LRRC specific genes were mainly enriched in positive regulation of transcription from RNA polymerase II promoter, plasma membrane, and ATP binding. The specific signaling pathways of LRRC were Wnt signaling pathway, gap junction, and glucagon signaling pathway, etc. The transcriptional and translational expression levels of genes including NFATC1, PRICKLE1, SOX17, and WNT6 related to Wnt signaling pathway were higher in rectal cancer (READ) tissues than normal rectal tissues. The PRICKLE1 mutation (c.C875T) and WNT6 mutation (c.G629A) were predicted as “D (deleterious)”. Expression levels of LEF1 and cytokinin D1 proteins: LRRC > PRC > NRRC > normal rectal tissue. Gene variants in the Wnt signaling pathway may be critical for the development of LRRC. The present study may provide a basis for the prediction of LRRC and the development of new therapeutic drugs.

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

Cited by 29 publications

References 43 publications

Agonists Specific for κ-Opioid Receptor Induces Apoptosis of HCC Cells Through Enhanced Endoplasmic Reticulum Stress

Agonists Specific for κ-Opioid Receptor Induces Apoptosis of HCC Cells Through Enhanced Endoplasmic Reticulum Stress

Identification and Validation of a Six Immune-Related Genes Signature for Predicting Prognosis in Patients With Stage II Colorectal Cancer

Whole-exome sequencing of rectal cancer identifies locally recurrent mutations in the Wnt pathway

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