School of Medicine Publications and Presentations

Document Type

Response or Comment

Publication Date

1-27-2023

Abstract

miR-205 is consistently downregulated in liver fibrosis, liver cirrhosis, and liver cancer, which indicates it may be a potential therapeutic restoration molecule to tackle liver diseases.

The spectrum of liver diseases presents a major public health concern that is widespread across the globe, accounting for 2 million deaths per year [1]. Among all liver diseases, the most common, nonalcoholic fatty liver disease (NAFLD), has been globally estimated to account for a quarter of all cases, ranging regionally from 14 to 32% [2]. In addition, liver cancer is the 16th most common cause of mortality worldwide [1]. Hence the imperativeness of novel therapeutic developments toward liver diseases is currently a clinically unmet need.

miRNAs have gained significant attention after their discovery in Caenorhabditis elegans. miRNAs have offered a new area of investigation ranging from the understanding of post-transcription regulatory genes to their role in various disease processes, including tumorigenesis. miRNAs are small noncoding RNA molecules that regulate post-transcriptional gene expression. Approximately 52.5% of human genes that code for miRNA are linked to cancer, hence the interest for those searching for potential therapeutic targets. There are about 38,589 miRNAs that have been identified specifically in 271 organisms. Such quantification has been gathered from miRbase, an online data base for miRNA sequences.

Biogenesis of miRNAs varies from organism to organism, depending on factors, such as the site where miRNAs are processed and the presence or absence of Drosha and DGCR8. Such processes follow a canonical pathway, albeit a noncanonical pathway has been suggested. It embarks its process at the nucleus and adjourns in the cytoplasm via Drosha and Dicer, respectively. As these processes continue, expression of argonaute (Ago) plays an imperative role in increasing miRNA stability post-transcriptionally. This suggests that Ago acts as a homeostatic component for miRNA maturity concentrations.

miRNAs with their respective classification will be named as miR-X, X being the classification. miRNAs found within the human body have been associated with a myriad of biochemical functions. For instance, the up and down regulation of miR-29a and miR-29b are associated with high glucose and insulin resistance [3]. In addition, miRNA-320 has also been found to have an effect on insulin resistance [4]. In terms of their role in lipids within the liver and hepatocytes, miRNA-10b has been proven to be a pioneer in abnormal retention of lipids. However, when it comes to healing after liver-damaging agents, miR-21 aids in liver regeneration and tissue repair when exposed to alcohol [5]. Furthermore, miR-122 and miR-155 are both associated with liver homeostasis [6] and autoimmune hepatitis [7] while miR-186 and miR-205 show their action in proliferation of hepatocellular carcinoma (HCC) [8]. In hepatitis B viral infections and liver diseases, various miRNAs, such as miR-15b, miR-16-1, miR-17, miR-18a, miR-19a, miR-19b, miR-20a, miR-21, miR-22, miR-23a, miR-23b, miR-25, miR-26a, miR-29b, miR-30, miR-31, miR-34a, miR-92a, miR-125b, miR-130a, miR-132, miR-133a, miR-141, miR-145, miR-146, miR-148a, miR-150, miR-152, miR-155, miR-181b, miR-192, miR-196a, miR-199b, miR-200, miR-200b, miR-200c, miR-205, miR-214, miR-219, miR-221, miR-223, miR-323, miR-372, miR-373, miR-375, miR-455, miR-501, miR-548, miR-602 and miR-604 have been implemented as biomarkers, therapeutics, direct/indirect inhibitors, and immunomodulators [9]. Altogether, various disease pathological processes including liver diseases are significantly influenced by miRNA dysregulation and miR-205 is consistently downregulated in almost all liver diseases. Hepatitis B is a viral infection (HBV X, HBx protein play crucial role) that attacks the liver and can cause both acute and chronic disease. A significantly lower expression of miR-205 was observed in HBV infected patients [10]. In addition, supplementation of miR-205 was able to remarkably inhibit the HBx-enhanced proliferation of hepatoma cells [11]. Considering these links, the prognostic and therapeutic role of miR-205 in liver diseases is the focus of this commentary article.

Role of miR-205 in liver diseases

miRNAs are small noncoding RNAs that act as a regulator of target messenger RNAs expression which is performed post-transcriptionally. miR-205 is localized in two locations in the human genome, Chr1 and Chr12 [12]; and its function is regulated with expressions of other genes through collaboration of various intertwined mechanisms [13]. Such miRNAs are relevant as its mode of mechanism either as oncogenes or tumor suppressors. Dysregulation of miR-205 in breast, prostate, skin, liver, gliomas, pancreatic, colorectal and renal cancer have been reported [14]. Furthermore, miR-205 sensitizes gemcitabine resistant pancreatic cancer cells and reduces tumor weight and growth [15], while in cervical cancer it induces lymph node metastasis when upregulated [16]. Therefore, delineating the specific role of miR-205 in liver diseases is highly warranted.

Liver fibrosis & cirrhosis

The development of liver fibrosis (LF) is aided by increased amounts of fibrillar extracellular matrix due to exposure a variety of liver tissue damaging agents. If untreated, LF progresses to liver cirrhosis (LCi). When the liver damaging agents emerge and stay prevalent, the healing process, hepatic fibrogenesis, subsequently acts opposite of its function, healing. When such liver damaging substances are chronically present long-term, so is the chronic-healing process, activating hepatic stellate cells to hyperactively secrete extracellular matrix. As a result, a chronic-cycle translating from LF to LCi and portal hypertension (a serious complication of LCi).

A highly sensitive serum miRNA panel evaluation confirmed there is no significant variation in miRNA expression in patients with chronic hepatitis C with LF (early or advanced stage) compared with no fibrosis patients [17]. miRNAs, such as miR-124, miR-200a, miR-200c, miR-205, miR-103a, and miR-15, were downregulated while miR-141, miR-155, miR-208a, miR-499, and miR-574 were upregulated in early-stage fibrosis (F0-F2). Similarly, miR-124, miR-155, miR-200c, miR-205, miR-103a, and miR-15 were downregulated whereas miR-141, miR-200a, miR-208a, miR-499, and miR-574 were upregulated in advanced stage fibrosis (F3-F4). In another study, profiles of differential expression of circulating miRNAs in LCi samples, miR-205 was downregulated while miR-195, miR-25, and miR-16 were upregulated. Interestingly, miR-205 is consistently downregulated in chronic hepatitis, LCi and HBV-positive HCC patient samples. A study on the progression of steatosis in liver of mice up on dietary responses of tissue-specific miR-205 confirmed that it regulates the signaling and metabolism in fibrosis and progresses to steatosis [18]. In one word, it can be stated that miR-205 is absent in LF and LCi conditions.

Nonalcoholic fatty liver disease

NAFLD is one of the most common liver-associated diseases and metabolic syndrome. NAFLD is an excessive accumulation and infiltration of adipocytes in the liver with ramifications similar to that of alcohol related fatty liver disease despite the absence of alcohol or lack thereof. There are various factors that influence the disease progression of NAFLD, some being known and others unknown. One such factor is that of hepatic fat accumulation and its lipotoxicity. The initial pathologic observation of NAFLD is the gradual increase of steatosis within hepatocytes. Factors that contribute to steatosis such as excessive triglyceride accumulation and an increased calorie diet, are some of the components that affect such hepatic fat accumulation and dramatically predisposes the individual to insulin resistance. As insulin resistance builds up an additional complication, lipolysis, arises, which leads to excessive free fatty acids circulating via blood vessels, steatosis and hyperinsulinemia.

Hu et al. [19], delineated the role and underlying mechanism of miR-205 in NAFLD. This study confirmed that over expression of miR-205 leads to the downregulation of liver triglycerides and enhancement of glycerol concentration, and thus suppressed lipid accumulation in high-fat diet-fed mice. Additionally, the miR-205 supplementation decreased body weight and liver mass. Further investigation also demonstrates that the overexpression of miR-205 alleviated lipid accumulation in OA-induced HepG2 and PH cells by targeting NEU1. Together, this study results suggest that miR-205/NEU1 can be a viable therapeutic target for treatment of NAFLD. In the series of experiments conducted on mouse models, it was found that miR-205 has an effect on transcription factor ZEBI, which has a role in liver metabolism and insulin resistance [20]. On the other hand, when NZ10 mice were predisposed with obesity, Type 2 diabetes and hepatic steatosis; fed with high protein fish oil diet and examined for the biochemical and physical functions, results showed that the diet prevented steatosis and reduced serum cholesterol and triglycerides, and the diet repressed the hepatic expression of fatty acid metabolic regulators like peroxisome proliferator activated receptor gamma co-activator-1, fatty acid synthase, fatty acid binding protein-4 and apolipoprotein A4 genes in these mice [18]. To prove miR-205 has the potential to act as a biomarker for other diseases such as Hidradenitis suppurativa, it was found that this, along with other RNAs, could be important for regulating skin and wound repair and age-related alterations [21].

Liver cancer

Liver cancer (LC), malignant components are linked to viral infections (hepatitis B and hepatitis C virus), obesity, and inflammation. However, viral infections do not lead directly to liver cancer. More frequently, such infections develop into LF and LCi which, when left untreated can progress to LC.

HCC is the most common type of primary liver cancer and one of the most aggressive malignances, indicating the imperative course of action in terms of prognosis and an improved treatment strategy. miRNA markers in HCC diagnosis evaluation suggests that five miRNAs (miR-124, miR-141, miR-205, miR-208a, and miR-499a) were significantly upregulated in the serum of HCC patients compared with chronic hepatitis with advanced LF [17]. Receiver operating characteristic curves were prepared for these miRNAs to identify the best miRNA for the diagnosis of HCC. This data disclosed that miR-205 exhibited highest under receiver operating characteristic: 0.9 (0.81–0.99) along with good sensitivity (85%) and specificity (85.19). Sun et al. [22], reported that miR-205 expression is low while CDKL3 is high in liver cancer tissues compared with normal healthy people. The in vitro and in vivo tumorigenic inhibitory effects of miR-205 is achieved via bone marrow mesenchymal stem cells-secreted exosomal delivery mechanism. It was shown that miR-205 exhibits an inhibitory effect in the progression of LC through the regulation of CDKL3 [22]. Heat shock protein family of Hsp40, its member being A1 (DNAJA1), have shown higher cell proliferation, invasion and angiogenesis in liver cancer cells. The mRNA levels of miR-205 and DNAJA1 are negatively corelated in liver cancer [23]. DNAJA1 along with EF1A1, has been suggested to promote proliferation of liver cancer cells, while miR-205 regulates DNAJA1 induced proliferation and metastasis of liver cancer cells. Together, this study advice miR-205-5p/EF1A1 axis may be a potential biomarker to predict the prognosis for liver cancer patients.

Interestingly enough, when miR-205 is downregulated, it promotes stem cell inhibition of HCC [24]. Similar effects have been observed in ubiquitin specific peptidase 7 (UPS7), an essential component for LC progression and regulation of p53, in that miR-205 acts as an inhibitor of UPS7 and helps channeling p53 into check of cell’s proliferation levels [25]. Furthermore, when the expression of miR-205 host gene role was investigated, it showed that miR-205-5p activates the pathway signaling of PI3K/AKT and helps in the suppression, migration, proliferation and invasion of hepatoblastoma cells [26].

HCC is highly correlated with the HBV infection. HBV X (HBx) protein plays crucial role in HCC development. In LC development, it has been suggested that HBx inhibits miR-205, enhancing tumor cell proliferation via hypermethylation of miR-205 [27]. HBx raises the levels of cellular cholesterol (metabolite of ACSL4), which can be blocked by miR-205 [28]. Low levels of miR-205 were negatively corelated with ACSL1 levels in clinical HCC patient tissue samples. miR-205 restoration is liver cancer cells involved in deregulation of lipid metabolism through targeting acyl-CoA synthetase long-chain family member 1 (ACSL1) [29]. All these events elucidate that miR-205 may play a role as a tumor suppressing miRNA whose down regulation may induce hepatocarcinogenesis [30].

Conclusion

The continuum of liver disease has been a critical component of global public health interest as its mortality and morbidity reaches millions of individuals each year. The function and activity miR-205 varies in various liver diseases; however, if applied optimally, it can act as a biomarker and therapeutic agent. Sufficient clinic trial investigations are required to confirm the biomarker/therapeutic potential of miR-205 in due course.

Comments

© 2023 Future Science Ltd

Publication Title

Future Drug Discovery

DOI

10.4155/fdd-2022-0012

Academic Level

faculty

Mentor/PI Department

Immunology and Microbiology

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