Abstract:Cancer is one of the lethal diseases that arise due to the molecular alterations in the cell. One of those alterations associated with cancer corresponds to differential expression of Farnesoid X receptor (FXR), a nuclear receptor regulating bile, cholesterol homeostasis, lipid, and glucose metabolism. FXR is known to regulate several diseases, including cancer and cardiovascular diseases, the two highly reported causes of mortality globally. Recent studies have shown the association of FXR overexpression with… Show more
“…K-Ras is a frequently mutated oncogene in CRC; its diverse mutations promote the activation of the MAPK pathway and cause spontaneous tumor development [ 126 ], and the aberrant activation of the PI3K/Akt/mTOR pathway strongly attenuates the efficacy of MAPK suppression [ 127 ]. It is reported that inhibition of K-Ras signaling in human colon cancer cells resulted in a strong increase in FXR levels [ 115 ] while FXR downregulation has been negatively related with PI3K signaling in human colon cancer [ 128 ].…”
Section: Dysregulated Signaling Pathways In Colorectal Cancer: the Em...mentioning
Colorectal cancer (CRC) ranks as the second among the causes of tumor death worldwide, with an estimation of 1.9 million new cases in 2020 and more than 900,000 deaths. This rate might increase by 60% over the next 10 years. These data are unacceptable considering that CRC could be successfully treated if diagnosed in the early stages. A high-fat diet promotes the hepatic synthesis of bile acids (BAs) increasing their delivery to the colonic lumen and numerous scientific reports correlate BAs, especially secondary BAs, with CRC incidence. We reviewed the physicochemical and biological characteristics of BAs, focusing on the major pathways involved in CRC risk and progression. We specifically pointed out the role of BAs as signaling molecules and the tangled relationships among their nuclear and membrane receptors with the big bang of molecular and cellular events that trigger CRC occurrence.
“…K-Ras is a frequently mutated oncogene in CRC; its diverse mutations promote the activation of the MAPK pathway and cause spontaneous tumor development [ 126 ], and the aberrant activation of the PI3K/Akt/mTOR pathway strongly attenuates the efficacy of MAPK suppression [ 127 ]. It is reported that inhibition of K-Ras signaling in human colon cancer cells resulted in a strong increase in FXR levels [ 115 ] while FXR downregulation has been negatively related with PI3K signaling in human colon cancer [ 128 ].…”
Section: Dysregulated Signaling Pathways In Colorectal Cancer: the Em...mentioning
Colorectal cancer (CRC) ranks as the second among the causes of tumor death worldwide, with an estimation of 1.9 million new cases in 2020 and more than 900,000 deaths. This rate might increase by 60% over the next 10 years. These data are unacceptable considering that CRC could be successfully treated if diagnosed in the early stages. A high-fat diet promotes the hepatic synthesis of bile acids (BAs) increasing their delivery to the colonic lumen and numerous scientific reports correlate BAs, especially secondary BAs, with CRC incidence. We reviewed the physicochemical and biological characteristics of BAs, focusing on the major pathways involved in CRC risk and progression. We specifically pointed out the role of BAs as signaling molecules and the tangled relationships among their nuclear and membrane receptors with the big bang of molecular and cellular events that trigger CRC occurrence.
“…Because the aberrant activation of the EMT process enhanced malignant progression (including metastasis, invasion, and chemoresistance) of various kinds of cancer cells ( Girisa et al, 2021 ; Cook and Wrana, 2022 ), to evaluate the association of CNTN -1 with malignant progression via EMT, the wound-healing assay, invasion assay, and drug sensitivity assay were carried out and the data showed that CNTN -1 overexpression dramatically enhanced the migration ( Figure 5A ), invasion ( Figure 5B ), and tolerance to cisplatin (A549- CNTN -1 vs. A549- CNTN -1-NC, Figure 5C ). These findings indicated that CNTN -1 upregulation promoted EMT phenotype, which enhanced the malignant progression of A549 cells.…”
Tumor metastasis and invasion are the main impediments to lung adenocarcinoma successful treatment. Previous studies demonstrate that chemotherapeutic agents can elevate the malignancy of cancer cells other than their therapeutic effects. In this study, the effects of transient low-dose cisplatin treatment on the malignant development of lung adenocarcinoma cells (A549) were detected, and the underlying epigenetic mechanisms were investigated. The findings showed that A549 cells exhibited epithelial-mesenchymal transition (EMT)-like phenotype along with malignant progression under the transient low-dose cisplatin treatment. Meanwhile, low-dose cisplatin was found to induce contactin-1 (CNTN-1) upregulation in A549 cells. Subsequently, we found that further overexpressing CNTN-1 in A549 cells obviously activated the EMT process in vitro and in vivo, and caused malignant development of A549 cells in vitro. Taken together, we conclude that low-dose cisplatin can activate the EMT process and resulting malignant progression through upregulating CNTN-1 in A549 cells. The findings provided new evidence that a low concentration of chemotherapeutic agents could facilitate the malignancy of carcinoma cells via activating the EMT process other than their therapeutic effects.
“…Numerous malignancies, including lung cancer, have been studied using FXR blockade [ 35 ]. In addition, MCA was identified as a naturally occurring FXR antagonist produced by the gut microbiota [ 36 ].…”
Lung cancer-related pleural fluid (LCPF) presents as a common complication with limited treatment. Beyond its function in lipid digestion, bile acid was identified as a potent carcinogen to stimulate tumor proliferation. Previous research indicated a correlation between serum bile acid levels and the risk of developing several gastrointestinal cancers. Our study identified elevated bile acid levels in LCPF and increased farnesoid X receptor (FXR) expression as bile acid nuclear receptors in pleural microvessels of lung adenocarcinoma. Additionally, LCPF stimulated the expression of proteins involved in bile acid synthesis and cholesterol metabolism in HUVECs including CYP7A1, StAR, HMGCR, and SREBP2. LCPF-induced endothelial motility and angiogenesis were counteracted by using β-muricholic acid as an FXR antagonist. Moreover, we investigated the efficacy of cholesterol-lowering medications, such as cholestyramine, fenofibrate, and atorvastatin, in regulating LCPF-regulated angiogenesis. Along with suppressing endothelial proliferation and angiogenesis, atorvastatin treatment reversed cholesterol accumulation and endothelial junction disruption caused by LCPF. Statin treatment inhibited LCPF-induced endothelial FXR expression as well as the downstream proteins RXR and SHP. Based on the positive findings of suppressing endothelial angiogenesis, our group further incorporated the effect of statin on clinical patients complicated with LCPF. A Kaplan–Meier analysis revealed the clinical benefit of statin exposure in patients with lung adenocarcinoma with LCPF. Conclusively, our study demonstrated the ability of statin to alleviate LCPF-induced angiogenesis in patients with LCPF via FXR modulation.
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