Liver cancers cause a high rate of death worldwide and hepatocellular carcinoma (HCC) is considered as the most common primary liver cancer. HCC remains a challenging disease to treat. Wnt/β-catenin signaling pathway is considered a tumor-promoting factor in various cancers; hence, the present review focused on the role of Wnt signaling in HCC, and its association with progression and therapy response based on pre-clinical and clinical evidence. The nuclear translocation of β-catenin enhances expression level of genes such as c-Myc and MMPs in increasing cancer progression. The mutation of CTNNB1 gene encoding β-catenin and its overexpression can lead to HCC progression. β-catenin signaling enhances cancer stem cell features of HCC and promotes their growth rate. Furthermore, β-catenin prevents apoptosis in HCC cells and increases their migration via triggering EMT and upregulating MMP levels. It is suggested that β-catenin signaling participates in mediating drug resistance and immuno-resistance in HCC. Upstream mediators including ncRNAs can regulate β-catenin signaling in HCC. Anti-cancer agents inhibit β-catenin signaling and mediate its proteasomal degradation in HCC therapy. Furthermore, clinical studies have revealed the role of β-catenin and its gene mutation (CTNBB1) in HCC progression. Based on these subjects, future experiments can focus on developing novel therapeutics targeting Wnt/β-catenin signaling in HCC therapy.

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Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways.

circMRPS35 promotes malignant progression and cisplatin resistance in hepatocellular carcinoma

circMRPS35 promotes malignant progression and cisplatin resistance in hepatocellular carcinoma.

ABSTRACT Chemoresistance in hepatocellular carcinoma (HCC) has been found to be influenced by exosomal transport of circRNAs. However, the role of circZFR in HCC chemoresistance still remains unclear. In the present study, circZFR was highly expressed in cisplatin (DDP)-resistant HCC cell lines and could regulate DDP resistance of the HCC cells. Also, circZFR was highly expressed in cancer-associated fibroblast (CAFs) and the exosome of CAFs. In addition, supplementation of CAFs in culture medium could promote DDP resistance of HCC cells. In vivo tumor xenograft experiments showed that knockdown of circZFR inhibited tumor growth and weakened DDP resistance, while CAFs-derived exosomes incubation increased the expression of circZFR, inhibited the STAT3/NF-κB pathway, promoted tumor growth, and enhanced DDP resistance. In general, CAFs-derived exosomes deliver circZFR to HCC cells, inhibit the STAT3/NF-κB pathway, and promote HCC development and chemoresistance. The results provided a new sight for the prevention and treatment of chemoresistance in HCC. Graphical abstract

https://www.tandfonline.com/doi/pdf/10.1080/21655979.2022.2032972?needAccess=true

Cancer-associated fibroblast exosomes promote chemoresistance to cisplatin in hepatocellular carcinoma through circZFR targeting signal transducers and activators of transcription (STAT3)/ nuclear factor -kappa B (NF-κB) pathway

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. HCC has high rates of death and recurrence, as well as very low survival rates. N6-methyladenosine (m6A) is the most abundant modification in eukaryotic RNAs, and circRNAs are a class of circular noncoding RNAs that are generated by back-splicing and they modulate multiple functions in a variety of cellular processes. Although the carcinogenesis of HCC is complex, emerging evidence has indicated that m6A modification and circRNA play vital roles in HCC development and progression. However, the underlying mechanisms governing HCC, their cross-talk, and clinical implications have not been fully elucidated. Therefore, in this paper, we elucidated the biological functions and molecular mechanisms of m6A modification in the carcinogenesis of HCC by illustrating three different regulatory factors ("writer", "eraser", and "reader") of the m6A modification process. Additionally, we dissected the functional roles of circRNAs in various malignant behaviors of HCC, thereby contributing to HCC initiation, progression and relapse. Furthermore, we demonstrated the cross-talk and interplay between m6A modification and circRNA by revealing the effects of the collaboration of circRNA and m6A modification on HCC progression. Finally, we proposed the clinical potential and implications of m6A modifiers and circRNAs as diagnostic biomarkers and therapeutic targets for HCC diagnosis, treatment and prognosis evaluation.

/pdf/the-functional-roles-cross-talk-and-clinical-implications-of-3cjj7mcw92.pdf

The functional roles, cross-talk and clinical implications of m6A modification and circRNA in hepatocellular carcinoma.

Background Hepatocellular carcinoma (HCC) is the leading cause of tumor-associated death in males and females worldwide. HCC is mostly diagnosed at advanced stages and the chemotherapeutic cisplatin is one of the major therapeutic options in the treatment of patients with treating advanced HCC. Despite several reports on HCC multidrug resistance, the underlying regulatory mechanisms are still unclear. Methods RT-PCR was performed to detect circRNA_102272, miR-326 and RUNX2 expression. The CCK8 assay was used to examine cell proliferation and cisplatin IC50 values. The luciferase reporter assay was performed to verify complementary combinations between circRNA_102272 and miR-326 and between miR-326 and RUNX2. Results CircRNA_102272 expression was upregulated in HCC tissues and cells. CircRNA_102272 knockdown suppressed HCC cell proliferation and decreased cisplatin-resistance. In addition, circRNA_102272 facilitated HCC cisplatin-resistance by regulating the miR-326/RUNX2 axis. Conclusion CircRNA_102272 is significantly increased in HCC tissues and cells and promotes HCC cell proliferation and cisplatin-resistance. More importantly, circRNA acts as a ceRNA to suppress the expression and activity of miR-326, leading to the increase in RUNX2 expression. By elucidating circRNA_102272 role and mechanism of action in HCC, our study provides insights and an opportunity to overcome cisplatin-resistance in HCC.

/pdf/circrna-102272-promotes-cisplatin-resistance-in-4ktg98cl45.pdf

Yonghai Guan

Papers

CircRNA_102272 Promotes Cisplatin-Resistance in Hepatocellular Carcinoma by Decreasing MiR-326 Targeting of RUNX2.