Secretory Clusterin: A Promising Target for Chemoresistance of Hepatocellular Carcinoma

2020 ◽  
Vol 20 (12) ◽  
pp. 1153-1165 ◽  
Author(s):  
Jie Zhang ◽  
Mengna Wu ◽  
Yuqing Xu ◽  
Qianqian Song ◽  
Wenjie Zheng
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Epithelial Mesenchymal Transition ◽  
Vital Role ◽  
Current Evidence ◽  
Drug Efflux ◽  
Mesenchymal Transition ◽  
Limited Efficacy ◽  
Promising Target ◽  
Chemotherapy Agents

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Chemoresistance remains the major factor for limited efficacy of the HCC treatment. Thus, exploring the mechanisms underlying drug resistance is of great importance. Secretory clusterin (sCLU), a stressactivated and ATP-independent molecular chaperone, is up-regulated in numerous tumors and correlated with malignant phenotypes. For HCC, the implication of sCLU was previously addressed in tumor growth, metastasis, as well as early diagnosis and poor prognosis. Notably, accumulating studies have emphasized its vital role in drug resistance of HCC. Depletion of sCLU synergistically could enhance the sensitivity of HCC cells to a variety of chemotherapy agents. Herein, we summarized the potential mechanisms accounting for the sCLU-induced chemoresistance, including promoting apoptosis evasion, facilitating epithelial-mesenchymal transition (EMT), maintaining the viability of cancer stem cell (CSC), enhancing drug efflux capacity, and regulating autophagic activities. The current evidence suggest that targeting sCLU might be a promising approach in overcoming chemoresistance of HCC.

scholarly journals Pharmacoproteomics Identifies Kinase Pathways that Drive the Epithelial-Mesenchymal Transition and Drug Resistance in Hepatocellular Carcinoma

Cell Systems ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 196-207.e7
Author(s):  
Martin Golkowski ◽  
Ho-Tak Lau ◽  
Marina Chan ◽  
Heidi Kenerson ◽  
Venkata Narayana Vidadala ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition

scholarly journals Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5126
Author(s):  
Enrique Rozengurt ◽  
Guido Eibl
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Recent Literature ◽  
Epithelial Mesenchymal Transition ◽  
Ductal Adenocarcinoma ◽  
Current Evidence ◽  
Src Tyrosine Kinase ◽  
Mesenchymal Transition ◽  
New Findings ◽  
Predominant Form

Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer, remains a devastating disease. The purpose of this review is to highlight recent literature on mechanistic and translational developments that advance our understanding of a complex crosstalk between KRAS, YAP and Src tyrosine kinase family (SFK) in PDAC development and maintenance. We discuss recent studies indicating the importance of RAS dimerization in signal transduction and new findings showing that the potent pro-oncogenic members of the SFK phosphorylate and inhibit RAS function. These surprising findings imply that RAS may not play a crucial role in maintaining certain subtypes of PDAC. In support of this interpretation, current evidence indicates that the survival of the basal-like subtype of PDAC is less dependent on RAS but relies, at least in part, on the activity of YAP/TAZ. Based on current evidence, we propose that SFK propels PDAC cells to a state of high metastasis, epithelial-mesenchymal transition (EMT) and reduced dependence on KRAS signaling, salient features of the aggressive basal-like/squamous subtype of PDAC. Strategies for PDAC treatment should consider the opposite effects of tyrosine phosphorylation on KRAS and SFK/YAP in the design of drug combinations that target these novel crosstalk mechanisms and overcome drug resistance.

scholarly journals ASIC1a Stimulates the Resistance of Human Hepatocellular Carcinoma by Promoting Epithelial-mesenchymal Transition via the AKT/GSK3β/Snail Signaling Pathway

2021 ◽  
Author(s):  
Yinci Zhang ◽  
Niandie Cao ◽  
Jiafeng Gao ◽  
Jiaojiao Liang ◽  
Yong Liang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Cell Migration ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Cell Migration And Invasion ◽  
Gsk 3Β ◽  
Hcc Cells

Abstract Background: The main obstacle to the cure of hepatocellular carcinoma (HCC) is multidrug resistance. Acid sensing ion channel 1a (ASIC1a) acts as a critical roles in all stages of cancer progression, especially invasion and metastasis as well as in resistance to therapy. Epithelial to mesenchymal transition (EMT) is a phenomenon in which epithelial cells transform into mesenchymal cells after being stimulated by extracellular factors and is closely related to tumor infiltration and resistance. Methods: Western blotting assay, Immunofluorescence (IF) staining, Immunohistochemistry (IHC) staining, MTT and colony formation assay and scratch healing assay were used to detect the level of ASIC1a and the cell proliferation, migration and invasion capabilities in this research.Results: In this research, we found that the protein of ASIC1a is overexpressed in HCC cancer tissues. In addition, we identified that the levels of ASIC1a are highly expressed in resistant HCC cells. Compared with the parental cells, EMT occurred more frequently in drug-resistant cells. Functional studies demonstrated that inactivation of ASIC1a restrained cell migration and invasion and enhanced the chemosensitivity of cells through EMT. In HCC cells, the overexpression of ASIC1a stimulates the up-regulation of EMT characterization molecular level and proliferation, migration and invasion capabilities and further induces drug resistance, while knocking down ASIC1a with short hairpin RNA (shRNA) has the opposite effect. Further investigations found that ASIC1a increased cell migration and invasion through EMT by regulating α and β-catenin, vimentin and fibronectin expression via AKT/GSK-3β/Snail pathway. Conclusions: Our study demonstrated that ASIC1a acts an important assignment in drug resistance of HCC through EMT via AKT/GSK-3β/Snail pathway, thereby lending a latent therapeutic objective and new ideas regarding to HCC.

scholarly journals SIX1 Down-Regulation Influence Drug Resistance, Epithelial-Mesenchymal Transcription Factors and Self-Renewal Capacity in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Pelin Balcik Ercin ◽  
Arzu Aysan ◽  
Nazli Salik ◽  
Esma Erciyas
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Liver Cancer ◽  
Expression Profile ◽  
Epithelial Mesenchymal Transition ◽  
Profile Analysis ◽  
Sorafenib Treatment ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Sine Oculis

Abstract Sine oculis homeoprotein 1 (SIX1) was discovered to exert an essential role in embryonic development and it was also identified to be re-activated in various types of mammalian cancer. Immunohistochemical and SIX1 gene expression analyses were performed to determine the prognostic role of SIX1 expression. SIX1 expression was suppressed by short hairpin RNA transduction in the SNU398 HCC cell line. The effects of SIX1 on proliferation, epithelial-mesenchymal transition, apoptosis, drug resistance, and sphere formation were assessed in SIX1 knock-down cells. The upregulated expression levels of SIX1 were revealed to be correlated with the stage of the disease in breast, colon and liver cancer, with liver cancer exhibiting the highest expression profile. SIX1 knockdown significantly affected the cell morphology, proliferation, downregulated the protein expression levels of ZEB1, ZEB2 and SNAI1 and upregulated the expression levels of TWIST1 in hepatocellular carcinoma cells. Furthermore, SIX1 knockdown cells were more sensitive to sorafenib treatment; however, the expression profile analysis of the drug resistance genes ABCB1, ABCC1 and ABCG2 did not explain this sensitivity. Finally, SIX1 knockdown cells were identified to have decreased CD90 levels and lost their sphere-forming ability, which is essential for cancer stem cell properties. Overall, these results indicated that SIX1 expression may be useful as a diagnostic marker for patients with HCC.

scholarly journals P53- and mevalonate pathway–driven malignancies require Arf6 for metastasis and drug resistance

2016 ◽  
Vol 213 (1) ◽  
pp. 81-95 ◽  
Author(s):  
Ari Hashimoto ◽  
Tsukasa Oikawa ◽  
Shigeru Hashimoto ◽  
Hirokazu Sugino ◽  
Ayumu Yoshikawa ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinases ◽  
Epithelial Mesenchymal Transition ◽  
Mevalonate Pathway ◽  
Mesenchymal Transition ◽  
Tumor Invasiveness ◽  
Geranylgeranyl Transferase ◽  
Prenylated Proteins ◽  
Chemotherapy Agents ◽  
Poor Patient Survival

Drug resistance, metastasis, and a mesenchymal transcriptional program are central features of aggressive breast tumors. The GTPase Arf6, often overexpressed in tumors, is critical to promote epithelial–mesenchymal transition and invasiveness. The metabolic mevalonate pathway (MVP) is associated with tumor invasiveness and known to prenylate proteins, but which prenylated proteins are critical for MVP-driven cancers is unknown. We show here that MVP requires the Arf6-dependent mesenchymal program. The MVP enzyme geranylgeranyl transferase II (GGT-II) and its substrate Rab11b are critical for Arf6 trafficking to the plasma membrane, where it is activated by receptor tyrosine kinases. Consistently, mutant p53, which is known to support tumorigenesis via MVP, promotes Arf6 activation via GGT-II and Rab11b. Inhibition of MVP and GGT-II blocked invasion and metastasis and reduced cancer cell resistance against chemotherapy agents, but only in cells overexpressing Arf6 and components of the mesenchymal program. Overexpression of Arf6 and mesenchymal proteins as well as enhanced MVP activity correlated with poor patient survival. These results provide insights into the molecular basis of MVP-driven malignancy.

scholarly journals The functional role of long noncoding RNA in resistance to anticancer treatment

2020 ◽  
Vol 12 ◽  
pp. 175883592092785
Author(s):  
Yidi Qu ◽  
Hor-Yue Tan ◽  
Yau-Tuen Chan ◽  
Hongbo Jiang ◽  
Ning Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Noncoding Rna ◽  
Epithelial Mesenchymal Transition ◽  
Drug Efflux ◽  
Mechanisms Of Resistance ◽  
Mesenchymal Transition ◽  
Damage Repair ◽  
Different Types ◽  
Anticancer Treatment

Chemotherapy is one of the fundamental methods of cancer treatment. However, drug resistance remains the main cause of clinical treatment failure. We comprehensively review the newly identified roles of long noncoding RNAs (lncRNAs) in oncobiology that are associated with drug resistance. The expression of lncRNAs is tissue-specific and often dysregulated in human cancers. Accumulating evidence suggests that lncRNAs are involved in chemoresistance of cancer cells. The main lncRNA-driven mechanisms of chemoresistance include regulation of drug efflux, DNA damage repair, cell cycle, apoptosis, epithelial-mesenchymal transition (EMT), induction of signaling pathways, and angiogenesis. LncRNA-driven mechanisms of resistance to various antineoplastic agents have been studied extensively. There are unique mechanisms of resistance against different types of drugs, and each mechanism may have more than one contributing factor. We summarize the emerging strategies that can be used to overcome the technical challenges in studying and addressing lncRNA-mediated drug resistance.

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