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Semi quantitative reverse transcription polymerase chain reaction analysis of mRNA expression of Shh pathway of CD133+ and CD133− of Hepa 1–6 cells. The difference of Shh mRNA and Smoh mRNA expressions between CD133+ Hepa 1–6 cells and CD133− Hepa 1–6 cells is statistically significant. Abbreviations: mRNA, messenger ribonucleic acid; Shh, sonic hedgehog; Ptch-1, patched homolog 1; Gli-1, glioma-associated oncogene homolog 1; Smoh, smoothened homolog; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
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The important role of cancer stem cells in carcinogenesis has been emphasized in research. CD133+ cells have been mentioned as liver cancer stem cells in hepatocellular carcinoma (HCC). Some researchers have proposed that the sonic hedgehog (Shh) pathway contributes to hepatocarcinogenesis and that the pathway activation occurs mainly in cancer ste...
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Context 1
... the difference of the expressions of Gli-1 protein, Ptch-1 protein, and Smoh protein between CD133+ cells and CD133-cells had no statistical significance (Table 2). Figure 3 demonstrates the RT-PCR expression of the four genes. The expressions of Shh and Smoh between these two kinds of cells has statistical significance. ...Citations
... In liver cancer, the Shh signalling pathway is found to be overactive in CD133-positive CSC's, playing a critical role in preserving CSC characteristics. Consequently, targeting the Shh signalling pathway may offer a promising approach to combat liver cancer [64]. In the context of glioma, CD133-positive CSCs exhibit an increased resistance to chemotherapy. ...
The Sonic Hedgehog (Shh) signalling pathway plays a critical role in normal development and tissue homeostasis, guiding cell differentiation, proliferation, and survival. Aberrant activation of this pathway, however, has been implicated in the pathogenesis of various cancers, largely due to its role in regulating cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells with the ability to self-renew, differentiate, and initiate tumour growth, contributing significantly to tumorigenesis, recurrence, and resistance to therapy. This review focuses on the intricate activity of the Shh pathway within the context of CSCs, detailing the molecular mechanisms through which Shh signalling influences CSC properties, including self-renewal, differentiation, and survival. It further explores the regulatory crosstalk between the Shh pathway and other signalling pathways in CSCs, highlighting the complexity of this regulatory network. Here, we delve into the upstream regulators and downstream effectors that modulate Shh pathway activity in CSCs. This review aims to cast a specific focus on the role of the Shh pathway in CSCs, provide a detailed exploration of molecular mechanisms and regulatory crosstalk, and discuss current and developing inhibitors. By summarising key findings and insights gained, we wish to emphasise the importance of further elucidating the interplay between the Shh pathway and CSCs to develop more effective cancer therapies.
... Notably, CSCs may be situated at the invasive edges of HCC nodules [58,59]. Additionally, HCC has been associated with a range of CSC markers 105]. Sukowati has highlighted the marked heterogeneity of HCC's CSCs, a trait that likely complicates efforts to effectively inhibit these cells [84]. ...
... Jeng reported that CD 133+ cells isolated from a mouse Hepa1-6-derived tumor showed a high expression of the components of the SHH signaling pathway [105]. They found that an activated SHH signaling pathway exists in CD133+ Hepa1-6 HCC cells in mice, with a downregulation of SHH mRNA and an upregulation of SMO mRNA [105]. ...
... Jeng reported that CD 133+ cells isolated from a mouse Hepa1-6-derived tumor showed a high expression of the components of the SHH signaling pathway [105]. They found that an activated SHH signaling pathway exists in CD133+ Hepa1-6 HCC cells in mice, with a downregulation of SHH mRNA and an upregulation of SMO mRNA [105]. CD133+ Hepa1-6 cells possess stem cell characteristics, including significantly higher colony proliferation and clonogenicity. ...
Simple Summary
Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer mortality. Treatment of HCC remains challenging, especially for those with advanced stages or those with postoperative recurrence. Molecular research of signaling pathways to afford new options of treatments is urgent. Moreover, among the various signaling pathways, the Sonic hedgehog (SHH) signaling pathway is implicated in multiple aspects of HCC, including cancer development, growth, invasiveness, recurrence, metastasis, the tumor microenvironment, and the maintenance of its cancer stem cells. The SHH signaling pathway also contributes to the resistance of HCC to chemotherapy, target therapy, and radiation therapy. This narrative review of the update studies reappraises the roles of SHH signaling in HCC. A deeper understanding of the SHH signaling pathway is crucial. It may provide more insights into the regulatory processes to establish novel treatments for HCC.
Abstract
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.
... The SHH signaling pathway (SHH) plays a pivotal role in the proliferation and invasiveness of HCC cells [48][49][50][51][52]. The activation of the SHH signaling pathway occurs after the HH ligand binds to its receptor Patched1 (PTCH1) [51,52]. ...
... Subsequently, GLI binds to the promoters in the nucleus in order to initiate the transcription of target genes, such as CYCLINs (cell proliferation), BCL2 (antiapoptotic) and SNAIL (EMT induction) [51,52]. Jeng et al. reported that the activation of the SHH signaling pathway is found in CD133+ Hepa1-6 HCC mouse cells [49]. SHH also affects the tumor microenvironment of HCC [51]. ...
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.
... CD133 regulates an array of cell signaling pathways, including Akt, B-cell lymphoma 2 (Bcl-2), Src, Ras, and its downstream effectors such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal Kinase (JNK), phosphoinositide 3-kinases (PI3K), signal transducer and activator of transcription (STAT) 3, and p38K [35,36]. It is also engaged with the Notch pathway, connected to dysregulated cell cycling and drug resistance [37,38] as well as with Shh facilitating anchorage-independent growth [39]. Additionally, CD133 physically associates with histone deacetylase HDAC6 and β-catenin leading to the formation of a functional module, thus activating Wnt signaling and promoting EMT, cancer cell migration, and metastasis [40]. ...
... Studies have identified morphologically and functionally distinct subpopulations of tumorinitiating PC cells, in preinvasive (PanIN) and invasive pancreatic neoplasms, marked by the expression of DCLK1 and CSC-like properties [116]. Microarray and siRNA screening assays have shown predominant expression of DCLK1 Hedgehog signaling pathway [17] Tumor differentiation [29] High-grade tumor [21] Shorter overall survival [21] Wnt/β-catenin pathway [29] Regulation of EMT [29] Higher tumor stage [21] Notch pathway [108] Invasiveness and Metastasis [29,30] Nodal metastasis [21] CD44 CD44 + Resistant [17,79] Crosstalk with RTK complexes [25] Increased GEM efflux via ABC transporter proteins [20] Lymph node metastasis [92] Lower overall survival [92] CD44 + CD24 + ESA + Notch signaling [109] Induction of EMT [79,110,111] Liver metastasis [92] Increased metastatic potential [91] Advanced TNM stage [92] High Ca19-9 levels [93] Poor differentiation [93] CD133 CD133 + CXCR4 + Resistant [112] Hedgehog signaling pathway [39] Tumor differentiation [23] Higher tumor stage (?) ...
The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ‘‘tumor debulking’’ rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting ‘natural agents’ that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.
... Independent studies confirmed ABCG2, CD133, GPC3, c-KIT, OCT4, NANOG and SOX2 expression to be up-regulated in SP cells and their tumorigenic ability was significantly enhanced [173]. Together, evidence has been obtained for side populations to express stemlike properties; however, the isolation of cancer stem cells from resection material has rarely been reported [8,174,175] partially due to the fact that a robust protocol for their successful isolation is still missing. A controversy exists regarding the purity and applicability of the SP assay for the isolation of CSCs. ...
Over the last decade research on cancer stem cells (CSC) significantly contributed to a better understanding of tumor biology. Given their similarity to normal stem cells, i.e. self-renewal and pluripotency the need arises to develop robust protocols for the isolation and characterization of CSCs. As with other malignancies, hepatic tumors are composed of a heterogeneous population of cells including liver cancer stem cells (LCSC). Yet, a precise understanding of why stem cells become cancerous is still lacking. There is unmet need to develop robust protocols for the successful isolation of LCSCs from human tissue resection material as to assist in the development of molecular targeted therapies. Here we review the research progress made in the isolation and characterization of LCSCs by considering a wide range of cell surface markers and sorting methods, as applied to side populations, microsphere cultures and the gradient centrifugation method. We emphasize the different fluorescence activated cell sorting methods and the possibility to enrich LCSCs by immunomagnetic beads. We review the specificity of functional assays by considering ABCG transporter and ALDH1 enzyme activities and evaluate the in vivo tumorigenicity of LCSCs in highly sensitive bioassays. Finally, we evaluate different LCSC markers in association with viral and non-viral liver disease and explore the potential of novel drug delivery systems targeting CD133, EpCAM, CD13 and CD90 for the development of molecular targeted therapies.
Graphical Abstract
... Recent evidence has indicated that HH signaling significantly facilitates liver development and regeneration, and activation of the pathway may contribute to HCC growth (Eichenmuller et al., 2009). One group proposed that HH signaling facilitates hepatocarcinogenesis, primarily in CD133 + Hepa 1-6 cells that have significantly higher colony proliferation and clonogenicity (Jeng et al., 2013). Others suggested that HH signal transduction is related to tumor chemoresistance and aggressiveness. ...
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and one of the leading causes of cancer-related deaths worldwide. A growing body of evidence supports the hypothesis that HCC is driven by a population of cells called liver cancer stem cells (LCSCs). LCSCs have been proposed to contribute to malignant HCC progression, including promoting tumor occurrence and growth, mediating tumor metastasis, and treatment resistance, but the regulatory mechanism of LCSCs in HCC remains unclear. Understanding the signaling pathways responsible for LCSC maintenance and survival may provide opportunities to improve patient outcomes. Here, we review the current literature about the origin of LCSCs and the niche composition, describe the current evidence of signaling pathways that mediate LCSC stemness, then highlight several mechanisms that modulate LCSC properties in HCC progression, and finally, summarize the new developments in therapeutic strategies targeting LCSCs markers and regulatory pathways.
... The activation of HH signaling enhances the G2-M transition following overexpression of cyclin B1 and cyclin-dependent kinase 1 (CDK1), facilitating cell proliferation [75]. Moreover, the overexpression of SMO mRNA is present in cancer stem cell CD133+ mouse liver cell line Hepa1-6 [76]. In addition, SMO polymorphisms in transplant recipients may increase the risk of HCC recurrence following liver transplantation [77]. ...
... SHH/SMO signaling pathway activates in cancer stem cells (CD133+) of the mouse hepatoma cell line Hepa1-6 [86]. CD133+ HCC cells with upregulated SMO mRNA have significantly higher colony proliferation and clonogenicity than CD133-HCC cells [76]. BMS-833923, a SMO inhibitor, significantly inhibits osteoblast differentiation of human mesenchymal stem cells (hMSCs) causing in a decrease of alkaline phosphate activity and a decrease of osteoblast-related gene expression and in vitro mineralization [133]. ...
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.
... Elevated SMO and GLI1 expressions were also observed in TUSC3-overexpressed cells while decreased in TUSC3-silenced cells. It has been reported that ABCC1 and CD133 are downstream targets of Hedgehog signaling pathway (28,41). When treated with Hedgehog signaling pathway inhibitor or activator, respectively, we found the tumor stemness and drug resistance were reversible against the phenotype caused by expression change of TUSC3 in CRC cells. ...
Tumor suppressor candidate 3 (TUSC3) is a coding gene responsible for N-glycosylation of many critical proteins. TUSC3 gene plays an oncogenic role in colorectal cancer (CRC), however, the role of TUSC3 in drug resistance of CRC is still unclear. The aim of this study is to investigate the biological function and molecular mechanism of TUSC3 in CRC drug resistance. The expression of TUSC3 in CRC is positively correlated to tumor stage in 90 paired clinical samples, and negatively associated with overall survival and disease-free survival of CRC patients. In vitro, TUSC3 promotes the formation of stemness and induces the drug resistance to 5-fluorouracil (5-FU) and cis-Dichlorodiammineplatinum(II) (DDP) in CRC cells. The tissue microarray assay and bioinformatic analysis indicates that TUSC3 may promote the expression of CD133 and ABCC1 via hedgehog signaling pathway. Treatment of Hedgehog signaling pathway agonist or inhibitor in TUSC3-silenced or TUSC3-overexpressed cells reverse the effects of TUSC3 in cellular stemness phenotype and drug resistance. Meanwhile, co-immunoprecipitation and immunofluorescence assays indicate a tight relationship between TUSC3 and SMO protein. Our data suggests that TUSC3 promotes the formation of cellular stemness and induces drug resistance via Hedgehog signaling pathway in CRC.
... In recent years, research has also progressed in other CSC signaling pathways. Researchers have a good understanding that MEK and JNK (Tong et al., 2015) regulate CSC self-renewal; Hedgehog (Jeng et al., 2013), NF-κB/snail (Nikolaou et al., 2015), IL-33/p38 , and ERK1/2 (Mahati et al., 2017) are related to CSC features; and ERK is also involved in the migration and invasion of CSCs , providing another explanation for the transfer mechanism of HCC. Although these signal pathway mechanisms vary widely, they have made outstanding contributions to the regulation of CSCs. ...
Cancer stem cells (CSCs) are subpopulations of cells with stem cell characteristics that produce both cancerous and non-tumorigenic cells in tumor tissues. The literature reports that CSCs are closely related to the development of hepatocellular carcinoma (HCC) and promote the malignant features of HCC such as high invasion, drug resistance, easy recurrence, easy metastasis, and poor prognosis. This review discusses the origin, molecular, and biological features, functions, and applications of CSCs in HCC in recent years; the goal is to clarify the importance of CSCs in treatment and explore their potential value in HCC-targeted therapy.
... Immunohistochemistry is the key to a correct diagnosis of dpHCC-ICC. Similar to how Hepa and AFP are reliable markers for HCC, [12] CK7, and CK19 are valuable markers for identifying ICC. [13] In our case, the HCC part showed positive results for Hepa, and the ICC part showed positive results for CK7 and negative results for Hepa. ...
We report a patient with double primary hepatocellular carcinoma and intrahepatic cholangiocarcinoma (dpHCC-ICC) who received surgical intervention at our institute. The incidence of dpHCC-ICC is extremely low. To the best of our knowledge, only 134 of these cases have been reported in the English literature worldwide.
