During mammalian embryonic development, primary cilia transduce and regulate several signaling pathways. Among the various pathways, Sonic hedgehog (SHH) is one of the most significant. SHH signaling ...remains quiescent in adult mammalian tissues. However, in multiple adult tissues, it becomes active during differentiation, proliferation, and maintenance. Moreover, aberrant activation of SHH signaling occurs in cancers of the skin, brain, liver, gallbladder, pancreas, stomach, colon, breast, lung, prostate, and hematological malignancies. Recent studies have shown that the tumor microenvironment or stroma could affect tumor development and metastasis. One hypothesis has been proposed, claiming that the pancreatic epithelia secretes SHH that is essential in establishing and regulating the pancreatic tumor microenvironment in promoting cancer progression. The SHH signaling pathway is also activated in the cancer stem cells (CSC) of several neoplasms. The self-renewal of CSC is regulated by the SHH/Smoothened receptor (SMO)/Glioma-associated oncogene homolog I (GLI) signaling pathway. Combined use of SHH signaling inhibitors and chemotherapy/radiation therapy/immunotherapy is therefore key in targeting CSCs.
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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death globally. The cancer stem cells (CSCs) of HCC are responsible for tumor growth, invasion, metastasis, recurrence, ...chemoresistance, target therapy resistance and radioresistance. The reported main surface markers used to identify liver CSCs include epithelial cell adhesion/activating molecule (EpCAM), cluster differentiation 90 (CD90), CD44 and CD133. The main molecular signaling pathways include the Wnt/β-catenin, transforming growth factors-β (TGF-β), sonic hedgehog (SHH), PI3K/Akt/mTOR and Notch. Patients with EpCAM-positive alpha-fetoprotein (AFP)-positive HCC are usually young but have advanced tumor-node-metastasis (TNM) stages. CD90-positive HCCs are usually poorly differentiated with worse prognosis. Those with CD44-positive HCC cells develop early metastases. Those with CD133 expression have a higher recurrence rate and a shorter overall survival. The Wnt/β-catenin signaling pathway triggers angiogenesis, tumor infiltration and metastasis through the enhancement of angiogenic factors. All CD133+ liver CSCs, CD133+/EpCAM+ liver CSCs and CD44+ liver CSCs contribute to sorafenib resistance. SHH signaling could protect HCC cells against ionizing radiation in an autocrine manner. Reducing the CSC population of HCC is crucial for the improvement of the therapy of advanced HCC. However, targeting CSCs of HCC is still challenging.
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Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated mortality worldwide. Hepatocarcinogenesis involves numerous interlinked factors and processes, including the Sonic ...hedgehog (Shh) signaling pathway, which participates in the carcinogenesis, progression, invasiveness, recurrence and cancer stem cell maintenance of HCC. The Shh signaling pathway is activated by ligands that bind to their receptor protein, Protein patched homolog (Ptch). The process of Shh ligand binding to Ptch weakens the inhibition of smoothened homolog (SMO) and activates signal transduction via glioma-associated oncogene homolog (Gli) transcription factors. The overexpression of Shh pathway molecules, including Shh, Ptch-1, Gli and SMO has been indicated in patients with HCC. It has also been suggested that the Shh signaling pathway exhibits cross-talk between numerous other signaling pathways. The inactivation of the Shh signaling pathway reduces HCC growth, increases radio-sensitivity and increases the beneficial effect of chemotherapy in HCC treatment. Therefore, inhibition of the Shh pathway may be an effective target therapy that can be used in the treatment of HCC. Key words: sonic hedgehog signaling pathway, hepatocellular carcinoma, recurrence, cancer stem cells
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Chronic liver injury could lead the formation of liver fibrosis, eventually some would develop to hepatocellular carcinoma (HCC), one of the leading malignancies worldwide. The aim of the study is to ...dissect the role of extracellular signal-regulated kinase 2 (ERK2) signaling in liver fibrosis and inflammation. The choline-deficient, ethionine-supplemented (CDE) diet could lead to fatty livers and generate oval cells, activate hepatocyte stellate cell (HSC) and recruit immune cells as the liver fibrosis model mice. WT and ERK2 deficient (ERK2
) mice were compared in terms of liver weight/body weight, liver function, liver fibrosis markers and the differential gene expression in hepatotoxicity. ERK2
mice display the less degree of liver fibrosis when compared to WT mice. The protein level of alpha smooth muscle (α-SMA) was reduced and several hepatocellular carcinoma-related genes such as MMP9, FoxM1 were down-regulated. In addition, the cell proliferation and the percentages of activated T cells were reduced in ERK2
mice upon liver injury. Therefore, ERK2 plays an important role in regulating liver cirrhosis and inflammation.
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The Role of Smoothened in Cancer Jeng, Kuo-Shyang; Sheen, I-Shyan; Leu, Chuen-Miin ...
International journal of molecular sciences,
09/2020, Volume:
21, Issue:
18
Journal Article
Peer reviewed
Open access
Smoothened (SMO) belongs to the Hedgehog (HH) signaling pathway, which regulates cell growth, migration, invasion and stem cells in cancer. The HH signaling pathway includes both canonical and ...noncanonical pathways. The canonical HH pathway functions through major HH molecules such as HH ligands, PTCH, SMO and GLI, whereas the noncanonical HH pathway involves the activation of SMO or GLI through other pathways. The role of SMO has been discussed in different types of cancer, including breast, liver, pancreatic and colon cancers. SMO expression correlates with tumor size, invasiveness, metastasis and recurrence. In addition, SMO inhibitors can suppress cancer formation, reduce the proliferation of cancer cells, trigger apoptosis and suppress cancer stem cell activity. A better understanding of the role of SMO in cancer could contribute to the development of novel therapeutic approaches.
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The magnetic nanoferrites (Fe 3 O 4 , CoFe 2 O 4 , and NiFe 2 O 4 ) were synthesized via hydrothermal method using an aloe vera plant extract solution. Magnetic nanoferrites were characterized using ...X-ray powder diffraction (XRD), vibrating sample magnetometer (VSM), field emission electron microscope (FESEM), transmission electron microscopy (TEM), and X-ray photon spectroscopy (XPS). Cytotoxicity was obtained using the water-soluble tetrazolium salt (WST) assay. X-ray diffraction analysis also demonstrated that the size range of the nanoferrites exhibited average diameters of 6-28 nm and also exhibited high crystallinity. Results showed that all the metallic nanoparticles (NPs) are magnetic with saturation values of Fe = 52 emu/g, Co = 33 emu/g, and Ni = 20.43 emu/g. The magnetic nanoferrites exhibited a high cell viability rate at high concentrations and as shown from the optical images of the cells signifies their nontoxic and biocompatibility property. From SEM and TEM, the spherical structure was noticeable and the particle size is also in accordance with XRD. The chemical states for each NP also confirmed the successful synthesis of each nanoferrite. Not to mention, the heating capabilities of the nanoferrites were investigated and showed significant temperature increase of 6 °C-8 °C and acceptable specific absorption rate (SAR) values. Interestingly, the results assure that the materials would be suitable as magnetic mediators for magnetic hyperthermia application for cancer treatment.
Highlights • Angiogeneic heterogeneity correlated with tumor size (T stage). • Heterogeneity of the extracellular matrix protein expression. • Heterogeneity of the immune microenvironment (NK cells, ...NKT, T cells and Myeloid-derived suppressor cells). • Heterogeneity of HCC cells in gene expression, genetic variation, signaling pathways and cancer stem cells. • We discuss heterogeneity of HCC in four sections as above and their potential therapies for HCC.
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The Role of Endoglin in Hepatocellular Carcinoma Jeng, Kuo-Shyang; Sheen, I-Shyan; Lin, Shu-Sheng ...
International journal of molecular sciences,
03/2021, Volume:
22, Issue:
6
Journal Article
Peer reviewed
Open access
Endoglin (CD105) is a type-1 integral transmembrane glycoprotein and coreceptor for transforming growth factor-β (TGF-β) ligands. The endoglin/TGF-β signaling pathway regulates hemostasis, cell ...proliferation/migration, extracellular matrix (ECM) synthesis and angiogenesis. Angiogenesis contributes to early progression, invasion, postoperative recurrence, and metastasis in hepatocellular carcinoma (HCC), one of the most widespread malignancies globally. Endoglin is overexpressed in newly formed HCC microvessels. It increases microvessel density in cirrhotic and regenerative HCC nodules. In addition, circulating endoglin is present in HCC patients, suggesting potential for use as a diagnostic or prognostic factor. HCC angiogenesis is dynamic and endoglin expression varies by stage. TRC105 (carotuximab) is an antibody against endoglin, and three of its clinical trials were related to liver diseases. A partial response was achieved when combining TRC105 with sorafenib. Although antiangiogenic therapy still carries some risks, combination therapy with endoglin inhibitors or other targeted therapies holds promise.
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HCC remains one of the leading causes of cancer-related death globally. The main challenges in treatments of hepatocellular carcinoma (HCC) primarily arise from high rates of postoperative recurrence ...and the limited efficacy in treating advanced-stage patients. Various signaling pathways involved in HCC have been reported. Among them, the Sonic hedgehog (SHH) signaling pathway is crucial. The presence of SHH ligands is identified in approximately 60% of HCC tumor tissues, including tumor nests. PTCH-1 and GLI-1 are detected in more than half of HCC tissues, while GLI-2 is found in over 84% of HCC tissues. The SHH signaling pathway (including canonical and non-canonical) is involved in different aspects of HCC, including hepatocarcinogenesis, tumor growth, tumor invasiveness, progression, and migration. The SHH signaling pathway also contributes to recurrence, metastasis, modulation of the cancer microenvironment, and sustaining cancer stem cells. It also affects the resistance of HCC cells to chemotherapy, target therapy, and radiotherapy. Reappraisal of the roles of the SHH signaling pathway in HCC may trigger some novel therapies for HCC.
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Abstract Background The aim of this study was to investigate whether <5 mm as the narrowest margin width may negatively affect a patient's outcome. Methods A prospective cohort study was designed. ...From January 1994 to July 2010, 196 patients with hepatocellular carcinoma undergoing central hepatectomy were divided into group A (n = 172; narrowest margin, ≥5 to <10 mm) and group B (n = 24; narrowest margin, <5 mm), and outcomes were compared. Results Significant differences between groups A and B included tumor size ( P = .057), infiltrative border ( P = .021), satellite lesions ( P = .021), and major perivascular abutment ( P = .028). Marginal recurrence occurred in 50% of the patients in group B but none of those in group A ( P < .001). There were no significant differences between the groups regarding recurrence, recurrence-related death, disease-free survival, and speed of recurrence, but a borderline significant difference was found regarding the cumulative probability of overall survival. After excluding early recurrence (within 1 year), group B had significantly lower cumulative probabilities of disease-free survival ( P = .020) and overall survival ( P < .001). Conclusions In central resections, narrowest margin width of <5 mm does not negatively affect recurrence and overall survival. However, it increases perimargin recurrence and inversely affects late outcomes.
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