Hepatocellular carcinoma (HCC), the primary malignancy of hepatocytes, is a diagnosis with bleak outcome. According to National Cancer Institute's SEER database, the average five-year survival rate of HCC patients in the US is 19.6% but can be as low as 2.5% for advanced, metastatic disease. When diagnosed at early stages, it is treatable with locoregional treatments including surgical resection, Radio-Frequency Ablation, Trans-Arterial Chemoembolization or liver transplantation. However, HCC is usually diagnosed at advanced stages when the tumor is unresectable, making these treatments ineffective. In such instances, systemic therapy with tyrosine kinase inhibitors (TKIs) becomes the only viable option, even though it benefits only 30% of patients, provides only a modest (~3months) increase in overall survival and causes drug resistance within 6months. HCC, like many other cancers, is highly heterogeneous making a one-size fits all option problematic. The selection of liver transplantation, locoregional treatment, TKIs or immune checkpoint inhibitors as a treatment strategy depends on the disease stage and underlying condition(s). Additionally, patients with similar disease phenotype can have different molecular etiology making treatment responses different. Stratification of patients at the molecular level would facilitate development of the most effective treatment option. With the increase in efficiency and affordability of "omics"-level analysis, considerable effort has been expended in classifying HCC at the molecular, metabolic and immunologic levels. This review examines the results of these efforts and the ways they can be leveraged to develop targeted treatment options for HCC.

Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification.

N6-methyladenosine (m6A) is the most abundant mRNA modification and is catalyzed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole catalytic subunit. Accumulating evidence in recent years reveals that METTL3 plays key roles in a variety of cancer types, either dependent or independent on its m6A RNA methyltransferase activity. While the roles of m6A modifications in cancer have been extensively reviewed elsewhere, the critical functions of METTL3 in various types of cancer, as well as the potential targeting of METTL3 as cancer treatment, have not yet been highlighted. Here we summarize our current understanding both on the oncogenic and tumor-suppressive functions of METTL3, as well as the underlying molecular mechanisms. The well-documented protein structure of the METTL3/METTL14 heterodimer provides the basis for potential therapeutic targeting, which is also discussed in this review.

/pdf/roles-of-mettl3-in-cancer-mechanisms-and-therapeutic-1ljcd09c4a.pdf

Roles of METTL3 in cancer: mechanisms and therapeutic targeting

Circular RNAs (circRNAs) have been increasingly demonstrated to function as novel promising therapeutic RNA molecules for diverse human diseases, including cancer. Although the important role of circRNAs has been well documented in HCC, the complex mechanisms of circRNAs in HCC need to be elucidated. Here, a novel circRNA circ_0001955 was identified from three GSE datasets (GSE7852, GSE94508, and GSE97322) as a differentially expressed circRNA between HCC and normal samples. We revealed that circ_0001955, TRAF6 and MAPK11 levels were increased, while miR-516a-5p levels were decreased in HCC tumor tissues compared to adjacent normal tissues. Knockdown of circ_0001955 repressed HCC tumor growth in vitro and in vivo, while overexpression of circ_0001955 exhibited the opposite effect. Circ_0001955 was identified as a sponge for miR-145-5p and miR-516a-5p, and TRAF6 and MAPK11 were demonstrated to be two target genes of miR-516a-5p. In conclusion, circ_0001955 facilitated HCC tumorigenesis by sponging miR-516a-5p to release TRAF6 and MAPK11 expression.

/pdf/circ-0001955-facilitates-hepatocellular-carcinoma-hcc-50bdhgymts.pdf

Circ_0001955 facilitates hepatocellular carcinoma (HCC) tumorigenesis by sponging miR-516a-5p to release TRAF6 and MAPK11

New insights into the pharmacological, immunological, and CAR-T-cell approaches in the treatment of hepatocellular carcinoma.

MicroRNAs (miRNAs) are fundamental post-transcriptional modulators of several critical cellular processes, a number of which are involved in host defense mechanisms. In particular, miRNA let-7 functions as an essential regulator of the function and differentiation of both innate and adaptive immune cells. Let-7 is involved in several human diseases, including cancer and viral infections. Several viral infections have found ways to dysregulate the expression of miRNAs. Extracellular vesicles (EV) are membrane-bound lipid structures released from many types of human cells that can transport proteins, lipids, mRNAs, and miRNAs, including let-7. After their release, EVs are taken up by the recipient cells and their contents released into the cytoplasm. Let-7-loaded EVs have been suggested to affect cellular pathways and biological targets in the recipient cells, and can modulate viral replication, the host antiviral response, and the action of cancer-related viruses. In the present review, we summarize the available knowledge concerning the expression of let-7 family members, functions, target genes, and mechanistic involvement in viral pathogenesis and host defense. This may provide insight into the development of new therapeutic strategies to manage viral infections. 

/pdf/microrna-let-7-and-viral-infections-focus-on-mechanisms-of-ul5vu8gr.pdf

MicroRNA let-7 and viral infections: focus on mechanisms of action

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.

/pdf/mechanisms-of-hepatocellular-carcinoma-progression-109se3qidj.pdf

Anna Galuza

Papers

Mechanisms of hepatocellular carcinoma progression.