Prognostic molecular markers in cholangiocarcinoma: A systematic review

Briggs, Christopher; Neal, Christopher P.; Mann, Christopher D.; Steward, William P.; Manson, Margaret M.; Berry, David P.

doi:10.1016/j.ejca.2008.08.024

Cited by 79 publications

(76 citation statements)

References 135 publications

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“…Currently, mucins are classified into membrane-associated mucins (MUC1, MUC3, MUC4, MUC12, MUC13, MUC15, MUC16, MUC17, MUC20 and MUC21), secreted gel-forming mucins (MUC2, MUC5AC, MUC5B, MUC6 and MUC19) and secreted non-gel-forming mucins (MUC7 and MUC8) by the HUGO nomenclature. Many previous studies have revealed that mucin expression profiles are a prognostic biomarker in some types of cancers Singh et al, 2008;Briggs et al, 2009). For instance, the expressions of MUC1, MUC2 and MUC5AC were statistically associated with a shorter survival time for pancreatic cancer patients in the United States (Takikita et al, 2009), suggesting that mucin functions not only to protect the normal epithelial surface from harsh environments but also to regulate cancer cell properties.…”

Section: Introductionmentioning

confidence: 99%

GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin

2010

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The Kru¨ppel-like zinc-finger protein GLI1 functions as a downstream transcription factor of Hedgehog signaling and plays a pivotal role in the cellular proliferation of many types of tumors, including pancreatic ductal adenocarcinoma (PDA). PDA develops from dysplastic lesions called pancreatic intraepithelial neoplasia (PanIN) through a multistep carcinogenesis process that changes its cellular characteristics, including a mucin expression profile. Increased expression of a gel-forming mucin, MUC5AC, was previously revealed as a major biomarker for the poor prognosis of PDA patients, but the molecular mechanisms responsible for its expression and correlation with poor prognosis are not fully understood. Here we show that MUC5AC is a direct transcriptional target of GLI1 in PDA cells. Overexpression of GLI1 enhanced MUC5AC expression, and a double knockdown of GLI1 and GLI2 suppressed endogenous MUC5AC expression in PDA cells. Luciferase reporter assays revealed that GLI1 and GLI2 can activate the MUC5AC promoter through its conserved CACCC-box-like cis-regulatory elements. We also found that GLI1-upregulated MUC5AC was expressed in the intercellular junction between cultured PDA cells and interfered with the membrane localization of E-cadherin, leading to decreased E-cadherin-dependent cell-cell adhesion and promoting the migration and invasion of PDA cells. Consistently, GLI1 induced the nuclear accumulation and target gene expression of b-catenin in a MUC5AC-dependent manner. Finally, immunohistochemical analysis revealed that GLI1 expression statistically correlated with MUC5AC expression and also with altered subcellular localization of E-cadherin and b-catenin in PanIN lesions and PDA. This evidence revealed a new aspect of GLI1 function in modulating E-cadherin/ b-catenin-regulated cancer cell properties through the expression of a gel-forming mucin.

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Section: Introductionmentioning

confidence: 99%

GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin

2010

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“…2 The mortality from intrahepatic cholangiocarcinoma is very high, with the 5-year survival rates being o15-20% in most series. 3,4 However, the exact molecular mechanisms of biliary epithelium malignant transformation are not well understood. Despite improved diagnostic and operative techniques, the prognosis of ICC remains poor.…”

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confidence: 99%

Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma

Hou

Dong

Tan

et al. 2011

Laboratory Investigation

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Intrahepatic cholangiocellular carcinomas (ICCs) are usually fatal neoplasms originating from bile duct epithelia. However, many cholangiocarcinoma cells are shown to be resistant to chemotherapeutic drugs, which induce cell apoptosis. The role of autophagy and the therapeutic value of autophagy-associated genes are largely unknown in ICC. Here, we showed that autophagy was activated in nutrient starvation and xenograft cholangiocarcinoma cells. Furthermore, expression of autophagic genes and their autophagic activity were higher in clinical ICC specimens than that in normal cholangiocytes separated by laser capture microdissection. Inhibition of autophagy by autophagy inhibitors or siRNA, cholangiocarcinoma cells showed detention of proliferation and increase of apoptosis during nutrient starvation. In addition, autophagy inhibitor treatment or knockdown of beclin 1 suppressed tumor growth and sensitized ICC cells to chemotherapeutic agent-induced cell death. In conclusion, our data showed that autophagy is activated in ICC, and inactivation of autophagy may lead to cell apoptosis and enhance chemotherapy sensitivity. Intrahepatic cholangiocellular carcinoma (ICC) is a malignant neoplasm originating from epithelium of the biliary tree with high mortality. 1 ICC accounts for 5-30% of all primary liver malignancies, and its incidence has been increasing over the last several decades. 2 The mortality from intrahepatic cholangiocarcinoma is very high, with the 5-year survival rates being o15-20% in most series. 3,4 However, the exact molecular mechanisms of biliary epithelium malignant transformation are not well understood. Despite improved diagnostic and operative techniques, the prognosis of ICC remains poor. 5 Indeed, ICC is a type of cancer highly resistant to conventional antineoplastic medicines, 4 which is partially attributed to the property of insensitivity to cell death induced by cytotoxic agents. It is well known that the avoidance of apoptosis is one of the hallmarks of cancer cells, 6 and that failure to induce apoptosis by anticancer treatments contributes to chemotherapeutic failure and tumor progression. Although autophagy, an alternative caspase-independent cell death program, 7 is thought to be used for cancer treatment, its underlying molecular mechanism is still controversial in antineoplastic therapy and also in tumor progression.Autophagy is a conserved catabolic process by which cells themselves digest their organelles. 8 Autophagy has emerged as a homeostatic mechanism regulating the turnover of long-lived or damaged proteins and organelles, and buffering metabolic stress induced under starvation conditions by recycling intracellular constituents. 9 Autophagosomes engulfing organelles then fuse with lysosomes and mature into autolysosomes. Autophagic processes have been well characterized in yeast, and 430 autophagy-related genes that encode the proteins executing autophagy have been identified in the field of yeast genetics. 6,7 The amino acids and fatty acids generated by autophagic degr...

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“…As mentioned above, it is known that most cases of CC have mutations in the TP53 gene; however, the role that this gene and P53 have in the prognosis of this cancer is not yet fully understood [16]. Some studies have shown that changes in the TP53 gene or in the P53 protein may, in this type of tumor, lead to changes in the underlying intracellular signaling cascades, thereby inducing resistance to therapies [16,35]. Other studies also indicate that MDM2 gene is overexpressed in most cases of CC, which can influence P53 expression and function.…”

Section: Molecular and Genetic Alterationsmentioning

confidence: 99%

“…Other studies also indicate that MDM2 gene is overexpressed in most cases of CC, which can influence P53 expression and function. Therefore, the inactivation of P53 by MDM2 plays an extremely important role in the resistance to apoptosis [16,[35][36][37].…”

Section: Molecular and Genetic Alterationsmentioning

confidence: 99%

Cholangiocarcinoma: from molecular biology to treatment

et al. 2015

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Cholangiocarcinoma is a rare tumor originating in the bile ducts, which, according to their anatomical location, is classified as intrahepatic, extrahepatic and hilar. Nevertheless, incidence rates have increased markedly in recent decades. With respect to tumor biology, several genetic alterations correlated with resistance to chemotherapy and radiotherapy have been identified. Here, we highlight changes in KRAS and TP53 genes that are normally associated with a more aggressive phenotype. Also IL-6 and some proteins of the BCL-2 family appear to be involved in the resistance that the cholangiocarcinoma presents toward conventional therapies. With regard to diagnosis, tumor markers most commonly used are CEA and CA 19-9, and although its use isolated appears controversial, their combined value has been increasingly advocated. In imaging terms, various methods are needed, such as abdominal ultrasound, computed tomography and cholangiopancreatography. Regarding therapy, surgical modalities are the only ones that offer chance of cure; however, due to late diagnosis, most patients cannot take advantage of them. Thus, the majority of patients are directed to other therapeutic modalities like chemotherapy, which, in this context, assumes a purely palliative role. Thus, it becomes urgent to investigate new therapeutic options for this highly aggressive type of tumor.

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Prognostic molecular markers in cholangiocarcinoma: A systematic review

Cited by 79 publications

References 135 publications

GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin

GLI1 facilitates the migration and invasion of pancreatic cancer cells through MUC5AC-mediated attenuation of E-cadherin

Inhibition of active autophagy induces apoptosis and increases chemosensitivity in cholangiocarcinoma

Cholangiocarcinoma: from molecular biology to treatment

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