Human hepatocellular carcinoma: Protection by melatonin

Abstract

Despite great scientific breakthroughs toward understanding the identity of human hepatocellular carcinoma (HCC) mechanistically, there are still no clinically efficient therapeutic methods for this cancer. Melatonin (N-acetyl-5-methoxytryptamine) is a multi-tasking hormone that has long been known for its anti-cancer activity against various human cancers including HCC, which is a focus of this review. PubMed database was searched for relevant articles with the keywords: hepatocellular carcinoma (HCC), melatonin, apoptosis, proliferation, invasion, angiogenesis, autophagy, oxidative stress, tumor immunity, and mitogen-activated protein kinase (MAPK) focusing on just human cell lines and English language articles. Melatonin inhibits apoptosis resistance and activates both extrinsic and intrinsic pathways of apoptosis in HCC. Melatonin induces ensoplasmic reticulum (ER)- and autophagy-mediated apoptosis in cancer cells. Melatonin works against cancer cell proliferation, motility, and invasiveness by modulating actions of a variety of transcription factors and related pathways. Melatonin also relieves an immunosuppressive state in HCC cancer cells through making a control over tumor-derived exosomes. Both pro-and anti-oxidative functions of melatonin are necessary for combating HCC. Combination of melatonin with chemotherapy could also provide cumulative effects on cancer cells. Melatonin exerts most of these roles by acting on the members of MAPK family.

Potential role of exosomes in cancer therapy

“…Hepatocellular carcinoma (HCC) is a primary malignancy of the liver, and occurs predominantly in patients with underlying chronic liver disease and cirrhosis . HCC is now the third leading cause of cancer deaths worldwide due to its frequent metastasis and easy relapsing postoperatively . Exosomes can transfer oncogenic miRNAs, including miR‐122 and miR‐32‐5p, to sensitive HCC cells, thereby inducing resistance to chemotherapy.…”

“…39 HCC is now the third leading cause of cancer deaths worldwide due to its frequent metastasis and easy relapsing postoperatively. 40 reported that lnc-ROR, a stress-responsive lncRNA, was selectively enriched by transforming growth factor beta in exosomes of HCC cells, and also regulated resistance to chemotherapy. 43 They also identified that exosomal lnc-VLDLR was significantly upregulated in HCC cells, and that it increased the expression level of ABCG2 (ATP-binding cassette, sub-family G member 2) to promote chemoresistance.…”

Reduced delivery of epididymal adipocyte‐derived exosomal resistin is essential for melatonin ameliorating hepatic steatosis in mice

“…N‐acetyl‐5‐methoxytryptamine, melatonin (MT) for short, is initially considered as a pineal hormone in maintaining day‐light rhythm . Recently, gastrointestinal tract has also been shown to secrete melatonin during night and daytime . However, intense investigations have gradually overthrew traditional standpoints and recognized melatonin as a broad‐spectrum regulatory molecule in multiple physiological activities, including improvements of reproduction, remissions of intestinal dysbacteriosis, anti‐inflammation, and anti‐cancer efforts .…”

“…On the other hand, melatonin has also been confirmed to protect liver during metabolic syndrome through various defined mechanisms . Melatonin triggers ER‐ and autophagy‐induced apoptosis in liver cancer, while it inhibits hepatocellular carcinoma proliferation and invasiveness via various transcription factors and signaling pathways . Notably, melatonin controls tumor‐generated exosomes to ameliorate the immune suppression of cancer cells, indicating that melatonin is able to regulate physiological state of hepatocytes via extrinsic pathways, particularly through exosomal modification .…”

“…23 Recently, gastrointestinal tract has also been shown to secrete melatonin during night and daytime. 24 However, intense investigations have gradually overthrew traditional standpoints and recognized melatonin as a broad-spectrum regulatory molecule in multiple physiological activities, including improvements of reproduction, 25,26 remissions of intestinal dysbacteriosis, 27 anti-inflammation, 28,29 and anti-cancer efforts. 30,31 In obese individuals and mice models, melatonin has also been identified to control the development of obesity, improve lipid metabolism, ameliorate hepatic oxidative stress and mitochondrial dysfunction, 3,4,[32][33][34][35][36] and alleviate local/systematical inflammation in different tissues and organs.…”