Exploring the role of m7G modification in Cancer: Mechanisms, regulatory proteins, and biomarker potential.

The dysregulation of N(7)-methylguanosine (m7G) modification is increasingly recognized as a key factor in the pathogenesis of cancers. Aberrant expression of these regulatory proteins in various cancers, including lung, liver, and bladder cancers, suggests a universal role in tumorigenesis. Studies have established a strong correlation between the expression levels of m7G regulatory proteins, such as Methyltransferase like 1 (METTL1) and WD repeat domain 4 (WDR4), and clinical parameters including tumor stage, grade, and patient prognosis. For example, in hepatocellular carcinoma, high METTL1 expression is associated with advanced tumor stage and poor prognosis. Similarly, WDR4 overexpression in colorectal cancer correlates with increased tumor invasiveness and reduced patient survival. This correlation underscores the potential of these proteins as valuable biomarkers for cancer diagnosis and prognosis. Additionally, m7G modification regulatory proteins influence cancer progression by modulating the expression of target genes involved in critical biological processes, including cell proliferation, apoptosis, migration, and invasion. Their ability to regulate these processes highlights their significance in the intricate network of molecular interactions driving tumor development and metastasis. Given their pivotal role in cancer biology, m7G modification regulatory proteins are emerging as promising therapeutic targets. Targeting these proteins could offer a novel approach to disrupt the malignant behavior of cancer cells and enhance treatment outcomes. Furthermore, their diagnostic and prognostic value could aid in the early detection of cancer and the selection of appropriate therapeutic strategies, ultimately enhancing patient management and survival rates. This review aims to explore the mechanisms of action of RNA m7G modification regulatory proteins in tumors and their potential applications in cancer progression and treatment. By delving into the roles of these regulatory proteins, we intend to provide a theoretical foundation for the development of novel cancer treatment strategies.

Intricate effects of post-translational modifications in liver cancer: mechanisms to clinical applications.

Liver cancer is a significant global health challenge, with hepatocellular carcinoma (HCC) being the most prevalent form, characterized by high incidence and mortality rates. Despite advances in targeted therapies and immunotherapies, the prognosis for advanced liver cancer remains poor. This underscores the urgent need for a deeper understanding of the molecular mechanisms underlying HCC to enable early detection and the development of novel therapeutic strategies. Post-translational modifications (PTMs) are crucial regulatory mechanisms in cellular biology, affecting protein functionality, interactions, and localization. These modifications, including phosphorylation, acetylation, methylation, ubiquitination, and glycosylation, occur after protein synthesis and play vital roles in various cellular processes. Recent advances in proteomics and molecular biology have highlighted the complex networks of PTMs, emphasizing their critical role in maintaining cellular homeostasis and disease pathogenesis. Dysregulation of PTMs has been associated with several malignant cellular processes in HCC, such as altered cell proliferation, migration, immune evasion, and metabolic reprogramming, contributing to tumor growth and metastasis. This review aims to provide a comprehensive understanding of the pathological mechanisms and clinical implications of various PTMs in liver cancer. By exploring the multifaceted interactions of PTMs and their impact on liver cancer progression, we highlight the potential of PTMs as biomarkers and therapeutic targets. The significance of this review lies in its potential to inform the development of novel therapeutic approaches and improve prognostic tools for early intervention in the fight against liver cancer.

Unraveling the crosstalk: circRNAs and the wnt signaling pathway in cancers of the digestive system.

Circular RNA (circRNA) is a unique type of noncoding RNA molecule characterized by its closed-loop structure. Functionally versatile, circRNAs play pivotal roles in gene expression regulation, protein activity modulation, and participation in cell signaling processes. In the context of cancers of the digestive system, the Wnt signaling pathway holds particular significance. Anomalous activation of the Wnt pathway serves as a primary catalyst for the development of colorectal cancer. Extensive research underscores the notable participation of circRNAs associated with the Wnt pathway in the progression of digestive system tumors. These circRNAs exhibit pronounced dysregulation across esophageal cancer, gastric cancer, liver cancer, colorectal cancer, pancreatic cancer, and cholangiocarcinoma. Furthermore, the altered expression of circRNAs linked to the Wnt pathway correlates with prognostic factors in digestive system tumors. Additionally, circRNAs related to the Wnt pathway showcase potential as diagnostic, therapeutic, and prognostic markers within the realm of digestive system tumors. This comprehensive review outlines the interplay between circRNAs and the Wnt signaling pathway in cancers of the digestive system. It seeks to provide a comprehensive perspective on their association while delving into ongoing research that explores the clinical applications of circRNAs associated with the Wnt pathway.

Enantioselective Self-Assembly of a Homochiral Tetrahedral Cage Comprising Only Achiral Precursors.

How Nature synthesizes enantiomerically pure substances from achiral or racemic resources remains a mystery. In this study, we aimed to emulate this natural phenomenon by constructing chiral tetrahedral cages through self-assembly, achieved by condensing two achiral compounds-a trisamine and a trisaldehyde. The occurrence of intercomponent CH⋅⋅⋅π interactions among the phenyl building blocks within the cage frameworks results in twisted conformations, imparting planar chirality to the tetrahedrons. In instances where the trisaldehyde precursor features electron-withdrawing ester side chains, we observed that the intermolecular CH⋅⋅⋅π forces are strong enough to prevent racemization. To attain enantioselective self-assembly, a chiral amine was introduced during the imine formation process. The addition of three equivalents of chiral amino mediator to one equivalent of the achiral trisaldehyde precursor formed a trisimino intermediate. This chiral compound was subsequently combined with the achiral trisamino precursor, leading to an imine exchange reaction that releasing the chiral amino mediator and formation of the tetrahedral cage with an enantiomeric excess (ee) of up to 75 %, exclusively composed of achiral building blocks. This experimental observation aligns with theoretical calculations based on the free energies of related cage structures. Moreover, since the chiral amine was not consumed during the imine exchange cycle, it enabled the enantioselective self-assembly of the tetrahedral cage for multiple cycles when new batches of the achiral trisaldehyde and trisamino precursors were successively added.

The Emerging, Multifaceted Role of WTAP in Cancer and Cancer Therapeutics.

Cancer is a grave and persistent illness, with the rates of both its occurrence and death toll increasing at an alarming pace. N6-methyladenosine (m6A), the most prevalent mRNA modification in eukaryotic organisms, is catalyzed by methyltransferases and has a significant impact on various aspects of cancer progression. WT1-associated protein (WTAP) is a crucial component of the m6A methyltransferase complex, catalyzing m6A methylation on RNA. It has been demonstrated to participate in numerous cellular pathophysiological processes, including X chromosome inactivation, cell proliferation, cell cycle regulation, and alternative splicing. A better understanding of the role of WTAP in cancer may render it a reliable factor for early diagnosis and prognosis, as well as a key therapeutic target for cancer treatment. It has been found that WTAP is closely related to tumor cell cycle regulation, metabolic regulation, autophagy, tumor immunity, ferroptosis, epithelial mesenchymal transformation (EMT), and drug resistance. In this review, we will focus on the latest advances in the biological functions of WTAP in cancer, and explore the prospects of its application in clinical diagnosis and therapy.

m6A-modification regulated circ-CCT3 acts as the sponge of miR-378a-3p to promote hepatocellular carcinoma progression.

Background: Circular RNA (circRNA) plays a critical role in tumour progression. Circ-CCT3, a particularly abundant circRNA, was proposed to be involved in tumorigenesis. However, the role of circ-CCT3 in hepatocellular carcinoma remains elusive.Methods: Here, circ-CCT3 (a circRNA derived from exons 3, 4 and 5 of the CCT3 gene, hsa_circ_0004680) was identified by circRNA microarray and validated by qRT-PCR. RNA immunoprecipitation (RIP) was performed to confirm the binding between ALKBH5 along with METTL3 and circ-CCT3. Methylated RNA Immunoprecipitation (MeRIP) was used to detect the N6-methyladenosine (m 2A) levels of circ-CCT3. CircRNAs in vivo precipitation, luciferase reporter assay, biotin-coupled microRNA capture, and fluorescence in situ hybridization were conducted to assess the interaction between circ-CCT3 and miR-378a-3p. The functions of circ-CCT3 in HCC were evaluated both in vitro and in vivo.Results: We demonstrated that circ-CCT3 was highly expressed in HCC which indicated the poor prognosis. Circ-CCT3 expression served as an independent risk factor for overall survival in patients with HCC. Knocking-down of circ-CCT3 inhibited the proliferation, invasion and migration of HCC cells, and angiogenesis of HUVEC. Mechanistically, ALKBH5 and METTL3 could bind and regulate m A-modification of circ-CCT3. Further, circ-CCT3 upregulated the expression of FLT-1 by sponging miR-378a-3p.Conclusions: Circ-CCT3 was significantly up-regulated in HCC and promoted liver cancer development via miR-378a-3p-FLT1 axis. It was also found that circ-CCT3 was under m A-modification mediated by ALKBH5 and METTL3. Our study highlights circ-CCT3 as a potential therapeutic target of HCC treatment, which provides a novel understanding on mechanisms of circRNAs in HCC progression.

Comprehensive analysis about prognostic and immunological role of WTAP in pan-cancer.

Background: Wilms tumor 1-associated protein (WTAP) plays a critical role in ribonucleic acid (RNA) methylation of N6 adenosine (m6A) modification, which is closely related with varieties of biological process. However, the role of WTAP in cancers remains to be determined. This study is designed to demonstrate the prognostic landscape of WTAP in pan-cancer and explore the relationship between WTAP expression and immune infiltration. Methods: Here, we investigated the expression level and prognostic role of WTAP in pan-cancer using multiple databases, including PrognoScan, GEPIA, and Kaplan-Meier Plotter. Then, applying the GEPIA and TIMER databases, we illustrated the correlations between WTAP expression and immune infiltration in tumors, especially liver hepatocellular carcinoma (LIHC), and esophageal carcinoma (ESCA). Results: WTAP had significant higher expression levels in tumor tissues of ESCA, LIHC, etc., while lower expression levels in those of bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), etc. And WTAP demonstrated multifaceted prognostic value in cancers. Of our interests, WTAP exerted a harmful effect on LIHC patient for overall survival (OS) and progression free survival (PFS). WTAP expression also significantly associated with the infiltration levels of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells (DC) in LIHC but not ESCA. Furthermore, combined analysis about WTAP expression level and immune cell specific gene markers implied WTAP correlates with regulatory cells (T reg) infiltration in LIHC and ESCA. Conclusion: The m6A regulator WTAP can serve as a prognostic biomarker for certain tumor types in pan-cancer and potentially result from immune cell infiltration.

ACSL4 reprograms fatty acid metabolism in hepatocellular carcinoma via c-Myc/SREBP1 pathway.

Lipid metabolic reprogramming plays a pivotal role in hepatocellular carcinoma (HCC) development, but the underlying mechanisms are incompletely characterized. Long chain acyl CoA synthetase 4 (ACSL4), a member of acyl-CoA synthetases (ACS) family, has been identified as a novel marker of alpha-fetoprotein-high subtype HCC and as an oncogene. Here, we identified a new function of ACSL4 in HCC lipid metabolism. ACSL4 can modulate de novo lipogenesis by accumulating intracellular triglycerides, cholesterols, and lipid droplets in HCC. Mechanistically, ACSL4 upregulates the master lipogenesis regulator sterol regulatory element binding protein 1 (SREBP1) and its downstream lipogenic enzymes in HCC cells via c-Myc. Moreover, SREBP1 is crucial for ACSL4-mediated regulation of lipogenesis as well as HCC cell proliferation and metastasis, as SREBP1 overexpression rescues lipogenic deficiency and decreased oncogenic capabilities associated with ACSL4 suppression in vitro and in vivo. Clinically, our data showed that the expression of ACSL4 was positively correlated with that of SREBP1 in HCC patients, and the combinational biomarkers showed strong predictive value for HCC. Together, our findings uncover a new mechanism by which ACSL4 modulates aberrant lipid metabolism and promotes the progression of HCC.

ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1.

BACKGROUND: N6-methyladenosine (m6A) modification is an emerging layer of epigenetic regulation which is widely implicated in the tumorigenicity of hepatocellular carcinoma (HCC), offering a novel perspective for investigating molecular pathogenesis of this disease. The role of AlkB homolog 5 (ALKBH5), one of the m6A demethylases, has not been fully explored in HCC. Here we clarify the biological profile and potential mechanisms of ALKBH5 in HCC. METHODS: Expression of ALKBH5 and its correlation with clinicopathological characteristics of HCC were evaluated using tissue microarrays and online datasets. And biological effects of ALKBH5 in HCC were determined in vitro and in vivo. Subsequently, methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA sequencing (RNA-seq), and following m6A dot blot, MeRIP-qPCR, RIP-qPCR or dual luciferase reporter assays were employed to screen and validate the candidate targets of ALKBH5. RESULTS: We demonstrated that ALKBH5 was down-regulated in HCC, and decreased ALKBH5 expression was an independent prognostic factor of worse survival in HCC patients. Functionally, ALKBH5 suppressed the proliferation and invasion capabilities of HCC cells in vitro and in vivo. Mechanistically, ALKBH5-mediated m6A demethylation led to a post-transcriptional inhibition of LY6/PLAUR Domain Containing 1 (LYPD1), which could be recognized and stabilized by the m6A effector IGF2BP1. In addition, we identified that LYPD1 induced oncogenic behaviors of tumors in contrast to ALKBH5. Dysregulation of ALKBH5/LYPD1 axis impelled the progression of HCC. CONCLUSION: Our study reveals that ALKBH5, characterized as a tumor suppressor, attenuates the expression of LYPD1 via an m6A-dependent manner in HCC cells. Our findings enrich the landscape of m6A-modulated tumor malignancy, and provide new insights into potential biomarkers and therapeutic targets of HCC treatment.

ACSL4 promotes hepatocellular carcinoma progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis.

Hepatocellular carcinoma (HCC) is a highly heterogeneous, multigene-driven malignant tumor. Long chain acyl-CoA synthetase 4 (ACSL4), an enzyme has pivotal roles in arachidonic acid (AA) metabolism. However, its function and the underlying molecular mechanisms in HCC are still not fully elucidated. Here, we identified ACSL4 as a novel marker for AFP high subtype HCC through transcriptome profiling. ACSL4 was frequently upregulated in HCC samples and associated with poor prognosis. Functionally, ACSL4 knockdown resulted in decreased cell growth, whereas ectopic ACSL4 expression facilitated tumor formation in vitro and in vivo. Mechanistically, ACSL4 stabilized the oncoprotein c-Myc through ubiquitin-proteasome system in an ERK/FBW7-dependent manner. Cell growth ability mediated by ACSL4 elevation was partly attenuated by c-Myc depletion using siRNA or its inhibitor 10058-F4. In contrast, the effects of ACSL4 silencing were partially reversed by c-Myc overexpression via FBW7 knockdown. Clinically, ACSL4 expression was positively correlated with c-Myc in HCC. In conclusion, ACSL4 is a novel marker for AFP high subtype HCC. Our data uncovered a new mechanism by which ACSL4 promotes HCC progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis and could be a valuable prognostic biomarker and a potential therapeutic target in HCC.

WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1.

BACKGROUND: N6-methyladenosine (m6A) methylation, a well-known modification with new epigenetic functions, has been reported to participate in the tumorigenesis of hepatocellular carcinoma (HCC), providing novel insights into the molecular pathogenesis of this disease. However, as the key component of m6A methylation, Wilms tumor 1-associated protein (WTAP) has not been well studied in HCC. Here we investigated the biological role and underlying mechanism of WTAP in liver cancer. METHODS: We determined the expression of WTAP and its correlation with clinicopathological features using tissue microarrays and the Cancer Genome Atlas (TCGA) dataset. And we clarified the effects of WTAP on HCC cells using cell proliferation assay, colony formation, Edu assay and subcutaneous xenograft experiments. We then applied RNA sequencing combined with gene expression omnibus (GEO) data to screen candidate targets of WTAP. Finally, we investigated the regulatory mechanism of WTAP in HCC by m6A dot blot assay, methylated RNA immunoprecipitation (MeRIP) assay, dual luciferase reporter assay, RNA immunoprecipitation (RIP) assay and Chromatin immunoprecipitation (ChIP) assay. RESULTS: We demonstrated that WTAP was highly expressed in HCC which indicated the poor prognosis, and that WTAP expression served as an independent predictor of HCC survival. Functionally, WTAP promoted the proliferation capability and tumor growth of HCC cells in vitro and in vivo. Furthermore, ETS proto-oncogene 1 (ETS1) was identified as the downstream effector of WTAP. The m6A modification regulated by WTAP led to post-transcriptional suppression of ETS1, with the implication of Hu-Antigen R (HuR) as an RNA stabilizer. Then ETS1 was found to inhibit the progression of HCC and could rescue the phenotype induced by WTAP deficiency. Moreover, WTAP modulated the G2/M phase of HCC cells through a p21/p27-dependent pattern mediated by ETS1. CONCLUSION: We have identified that WTAP is significantly up-regulated in HCC and promotes liver cancer development. WTAP-guided m6A modification contributes to the progression of HCC via the HuR-ETS1-p21/p27 axis. Our study is the first to report that WTAP-mediated m6A methylation has a crucial role in HCC oncogenesis, and highlights WTAP as a potential therapeutic target of HCC treatment.

Targeting Mybbp1a suppresses HCC progression via inhibiting IGF1/AKT pathway by CpG islands hypo-methylation dependent promotion of IGFBP5.

BACKGROUND: Myb-binding protein 1A (Mybbp1a) is a nucleolar protein that can regulate rRNA metabolism, the stress response and carcinogenesis. However, the function of Mybbp1a in the progression of hepatocellular carcinoma (HCC) is unclear. We aimed to determine the role of Mybbp1a in HCC and the underlying mechanism. METHODS: We investigated the function of Mybbp1a in HCC cell models and the xenograft mouse model. The relationship between Mybbp1a and IGFBP5 was found through expression profile chip. The molecular mechanism of Mybbp1a regulating IGFBP5 was proved through CO-IP, CHIP, Bisulfite Sequencing and Pyrosequencing. FINDINGS: In this study, we observed that Mybbp1a was overexpressed in HCC tissues and associated with the poor prognosis of HCC patients. Suppression of Mybbp1a led to a reduction in the proliferation and migration ability of HCC cells through inhibiting the IGF1/AKT signaling pathway. Further study found that Mybbp1a could form a complex with DNMT1 and induce aberrant hyper-methylation of CpG islands of IGFBP5, which inhibits secretion of IGFBP5 and then activates IGF1/AKT signaling pathway. INTERPRETATION: These findings extend our understanding of the function of Mybbp1a in the progression of HCC. The newly identified Mybbp1a may provide a novel biomarker for developing potential therapeutic targets of HCC. FUND: Science Technology Department of Zhejiang Province (No. 2015C03034), National Health and Family Planning Commission of China (No. 2016138643), Innovative Research Groups of National Natural Science Foundation of China (No. 81721091), Major program of National Natural Science Foundation of China (No. 91542205).

An Efficient Combination Immunotherapy for Primary Liver Cancer by Harmonized Activation of Innate and Adaptive Immunity in Mice.

Immunotherapy with checkpoint inhibitors for liver cancer, while active in many clinical trials worldwide, may have uncertain outcomes due to the unique immunotolerant microenvironment of the liver. In previous experiments, we unexpectedly identified a robust liver tumor-preventive effect of a synthetic double-stranded RNA, polyinosinic-polycytidylic acid (polyIC), in mice. Herein we further demonstrate that polyIC given at the precancer stage effectively prevented liver tumorigenesis by activating natural killer cells, macrophages, and some T-cell subsets; no inhibitory effect was observed on tumor progression if injected after tumor initiation. Nevertheless, polyIC administration potently induced programmed death ligand 1 (PD-L1) expression in liver sinusoid endothelial cells, which prompted us to test a combined treatment of polyIC and PD-L1 antibody (Ab). Although injecting PD-L1 Ab alone did not show any therapeutic effect, injection of polyIC sensitized the hepatic response to PD-L1 blockade. Combination of polyIC and PD-L1 Ab resulted in sustained accumulation of active cluster of differentiation 8 cytotoxic T cells and robust liver tumor suppression and conferred a survival advantage in mice. These preclinical data in animal models suggest that, despite the low efficacy of PD-L1/PD-1 blockade alone, careful design of mechanism-based combinatorial immunotherapeutic protocols may shift the paradigm in liver cancer treatment by coordinating maximal activation of multiple innate and adaptive immune functions. Conclusion: We provide proof of principle for the development of an efficient prevention strategy of liver tumorigenesis and a powerful combination immunotherapy for primary liver cancer.

Over Expression of Long Non-Coding RNA PANDA Promotes Hepatocellular Carcinoma by Inhibiting Senescence Associated Inflammatory Factor IL8.

It has been reported that long non-coding RNA PANDA was disregulated in varieties types of tumor, but its expression level and biological role in hepatocellular carcinoma (HCC) remains contradictory. We detected PANDA expression in two independent cohorts (48 HCC patients following liver transplantation and 84 HCC patients following liver resection), and found that PANDA was down-regulated in HCC. Thereafter we explored its function in cancer biology by inversing its low expression. Surprisingly, overexpression of PANDA promoted HCC proliferation and carcinogenesis in vitro and in vivo. Mechanistically, PANDA repressed transcriptional activity of senescence associated inflammatory factor IL8, which leaded to inhibition of cellular senescence. Therefore, our research help to better understand the complex role of PANDA in HCC, and suggest more thoughtful strategies should be applied before it can be treated as a potential therapeutic target.

KCTD11 inhibits growth and metastasis of hepatocellular carcinoma through activating Hippo signaling.

A lack of effective prognostic biomarkers and molecular targets is a serious problem in hepatocellular carcinoma. KCTD11, reported as a tumor suppressor, are still not well understood. In this study, KCTD11 was found low-expressed in HCC tissues and cell lines. The HCC patients with low expression of KCTD11 suggested shorter overall survival. We found KCTD11 inhibiting cell proliferation in vitro and tumor growth in vivo, by activating p21 and repressing cycle related proteins. KCTD11 also inhibited cell adhesion by decreasing CTGF and CLDN1. We found CTGF binding COL3A1 in HCCLM3, which might lead to reduction of COL3A1 expression. KCTD11 also inhibited cell migration and invasion in HCC, by repressing MMPs and EMT. We found the tumor suppression function of KCTD11 was at least partly through activating Hippo pathway in HCC. Base on the enhanced Hippo pathway, KCTD11 could activate p21 by stabilizing p53 or promoting the MST1/ GSK3ß/p21 signaling in HCC. Overall, these results suggest that KCTD11 works as a tumor suppressor and owns prognostic and therapeutic potentials in HCC.

Expression and Critical Role of Interleukin Enhancer Binding Factor 2 in Hepatocellular Carcinoma.

Interleukin enhancer binding factor 2 (ILF2), a transcription factor, regulates cell growth by inhibiting the stabilization of mRNA. Currently, its role has gained recognition as a factor in the tumorigenic process. However, until now, little has been known about the detailed role ILF2 plays in hepatocellular carcinoma (HCC). In this study, we investigated the expression levels of ILF2 in HCC tissue with Western blot and immunohistochemical assays. To examine the effect of ILF2 on liver cancer cell growth and apoptosis, small interfering RNAs (siRNAs) targeting ILF2 were recombined to create lentiviral overexpression vectors. Our results showed higher expression levels of ILF2 mRNA and ILF2 protein in HCC tissue compared with matched peritumoral tissue. Expression of ILF2 may regulate cell growth and apoptosis in liver cancer cells via regulation of B-cell lymphoma 2 (Bcl-2), Bcl-2 related ovarian killer (Bok), Bcl-2-associated X protein (BAX), and cellular inhibitor of apoptosis 1 (cIAP1). Moreover, we inoculated nude mice with liver cancer cells to investigate the effect of ILF2 on tumorigenesis in vivo. As expected, a rapid growth was observed in cancer cells inoculated with a lentiviral vector coding Flag-ILF2 (Lenti-ILF2) compared with the control cells. Hence, these results promote a better understanding of ILF2's potential role as a therapeutic target in HCC.

TAZ regulates cell proliferation and sensitivity to vitamin D3 in intrahepatic cholangiocarcinoma.

The transcriptional coactivator with PDZ binding motif (TAZ) is reported as one of the nuclear effectors of Hippo-related pathways. TAZ is found overexpressed in many primary tumors and could regulate many biological processes. However, little is known about the role of TAZ in Intrahepatic Cholangiocarcinoma (ICC). In this study, we found that TAZ is expressed more in ICC tissues than in peritumoral tissue, and a robust expression of TAZ is correlated with a lower overall survival rate of ICC patients after hepatectomy. TAZ knockdown results in an increase in cell apoptosis, a promotion of cell-cycle arrest and a decrease in tumor size and weight in vivo through an increased expression of p53. Vitamin D3 can also inhibit cell proliferation by promoting p53 expression in ICC cells. A reduction in TAZ can also enhance the sensitivity of tumor cells to vitamin D by regulating the p53/CYP24A1 pathway. In conclusion, TAZ is associated with the proliferation and drug-resistance of ICC cells, and could be a novel therapeutic target for the treatment of ICC.

Downregulation of Peptidylprolyl isomerase A promotes cell death and enhances doxorubicin-induced apoptosis in hepatocellular carcinoma.

Peptidylprolyl isomerase A (PPIA) is a peptidyl-prolyl cis-trans isomerase that is known to play a critical role in the development of many human cancers. However, the precise biological function of PPIA in hepatocellular carcinoma (HCC) remains largely unclear. In this study, lentiviral overexpression vectors and small interfering RNA knockdown methods were employed to investigate the biological effects of PPIA in HCC. PPIA levels in HCC tissues and peritumoral tissues were detected by real-time Polymerase Chain Reaction (RT-PCR), Western blotting, and immunohistochemistry. Our results indicate that PPIA levels were significantly higher in the HCC tissues compared to the matched peritumoral tissues. Moreover, PPIA expression was significantly associated with tumor size in these tissues. Interestingly, serum PPIA (sPPIA) levels were significantly higher in healthy controls compared to the HCC patients. Knockdown or overexpression of PPIA was shown to downregulate and upregulate cell growth, respectively. Moreover, PPIA siRNA knockdown appears to promote doxorubicin-induced apoptosis in HCC cells, altering the expression of downstream apoptotic factors. In summary, our results indicate that PPIA may play a pivotal role in HCC by regulating cell growth and could serve as a novel marker and therapeutic molecular target for HCC patients.