Systemic characterization of genomic alterations into signaling pathways helps to understand the molecular pathogenies of colorectal cancer; however, their clinical implications remain unclear. Here, 128 patients with metastatic colorectal cancer (mCRC) receiving targeted next generation sequencing were retrospectively enrolled to analyze the impact of altered oncogenic pathways on clinical outcome. The datasets from Memorial Sloan Kettering Cancer Center were used for validation. In 123 patients with non-MSI-high tumor, the most common mutated gene was TP53 (84.6%), followed by APC (78.0%), KRAS (49.6%), and SMAD4 (22.8%). When mutated genes were allocated into signaling pathways defined as The Cancer Genome Atlas Pan-Cancer Analysis Project, alterations of cell cycle, Wnt, p53, RTK-RAS, PI3K, TGF-β, Notch, and Myc pathways were identified in 88%, 87%, 85%, 75%, 28%, 26%, 17%, and 10% of mCRC tissues, respectively. The survival analyses revealed that Myc and TGF-β pathway alterations were associated with a shorter overall survival (OS) (hazard ratio [HR]: 2.412; 95% confidence interval [CI]: 1.139–5.109; p = 0.018 and HR: 2.754; 95% CI: 1.044–7.265; p = 0.033, respectively). The negative prognostic impact of altered TGF-β pathway was maintained in patients receiving an anti-EGFR antibody. The OS of patients with mCRC carrying MYC and BRAF mutation was shorter than those with either MYC or BRAF mutation (HR: 4.981, 95% CI: 0.296–83.92; p = 0.02). These findings have clinical implications, such as prognosis prediction, treatment guidance, and molecular-targeted therapy development.
Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare but aggressive subtype of renal cancer associated with germline or somatic mutations of the FH gene. The histology demonstrates a broad range of morphologic patterns with loss of FH immunostaining. There is no standard therapy approved for FH-deficient RCC, and treatment is often extrapolated from other subtypes of RCC. With a better understanding of the molecular mechanism and pathogenesis, more studies including this population are ongoing. We reported a 33-year-old man with no relevant family history diagnosed with locally advanced FH-deficient RCC and who later developed distant metastasis. He received erlotinib-bevacizumab combination therapy and achieved a partial response. We also performed a literature review of FH-deficient RCC.
MicroRNA‐451 (miR‐451) modulates erythroid differentiation and human malignancy. However, its role in the regulation of vascular smooth muscle cell (VSMC) function in health and disease remains unclear. Using a combination of in vitro system and in vivo investigations on experimental animals and human clinical specimens to clarify the function of miR‐451 in VSMCs. In situ hybridization showed that miR‐451 was significantly expressed in VSMCs of the medial layer in diseased human coronary arteries. In vitro study, culturing VSMCs on fibrillar collagen increased miR‐451 level and led to low proliferative and anti‐inflammatory responses; these effects were diminished by anti‐miR‐451. We identified that Rab5a was targeted by miR‐451 to modulate VSMC proliferation and inflammation. In rat studies, overexpression of miR‐451 and lentivirus‐mediated Rab5a silencing markedly suppressed the neointima formation induced by balloon injury. The level of circulating miR‐451 of blood plasma in patients with coronary artery disease and apolipoprotein E knockout mice (ApoE‐/‐) fed with a high‐cholesterol diet was significantly lower than control group. Increase of circulating miR‐451 by tail vein injection with agomir‐451 in ApoE‐/‐ mice fed with a high‐cholesterol diet for three months decreased atherosclerotic lesion formation. Our findings indicate that miR‐451, by targeting Rab5a, inhibits VSMC proliferation and inflammation in cultured VSMCs in vitro and suppresses neointima formation in injured arteries in vivo.
Atherosclerosis is a chronic inflammatory disease that results from imbalance of high‐density lipoprotein (HDL) cholesterol metabolism and a maladaptive immune response driven by the accumulation of cholesterol‐laden macrophages in the artery wall. MicroRNA‐146a (miR‐146a) serves as anti‐inflammatory function in a variety of cell types, but the underlying mechanisms of miR‐146a in atherosclerosis still remain unclear. In the present study, we assessed the impact of the genetic deficiency of miR‐146a in a mouse model of atherosclerosis and determined the miR‐146a‐mediated balance of cholesterol metabolism in macrophages. In comparison with miR‐146a+/+ApoE−/− mice fed with high‐cholesterol diet for 10 weeks, miR‐146a−/−ApoE−/− mice showed an increase number and area of atherosclerotic plaques, lipid content, pro‐inflammatory cytokines and abundant macrophages accumulated in the plaques. In addition, miR‐146a−/−ApoE−/− mice also showed decrease in HDL levels. Bone marrow chimera experiments indicated a major effect of miR‐146a deficiency on lesional macrophages. Bone marrow derived‐macrophages (BMDMs) were isolated from miR‐146a−/−ApoE−/− and miR‐146a+/+ApoE−/− mice to stimulated with oxidized low‐density lipoprotein (oxLDL). In comparison with BMDMs of miR‐146a+/+ApoE−/−, BMDMs of miR‐146a−/−ApoE−/− showed a significant oxLDL uptake and reduction in cholesterol efflux capacity. The expression of cholesterol transporters, including the ATP‐binding cassette sub‐family A1 (ABCA1) and sub‐family G1 (ABCG1) were significantly decreased in BMDMs of miR‐146a−/−ApoE−/−. By using the global gene expression analysis and argonaute‐2 immunoprecipitation, we demonstrated that toll‐like receptor 4 (TLR4) is directly targeted by miR‐146a. Overexpression of miR‐146a and silence of TLR4 not only increased the expression of ABCA1 and ABCG1, but also increased the cholesterol efflux capacity and reduced the oxidized LDL uptake. These data demonstrated that miR‐146a is involved in regulation of ABCA1 and ABCG1 by targeting TLR4, and that maintains the balance of HDL cholesterol metabolism to protect against the atherosclerosis. MiR‐146a is a potential target in treatment of atherosclerotic vascular disease.Support or Funding InformationMOST 104‐2321‐B‐400‐020‐MY3 (to L.‐J. C.) and MOST 104‐2321‐B‐400‐017 (to J.‐J. C.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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