Conjugated Linoleic Acid Treatment Attenuates Cancerous features in Hepatocellular Carcinoma Cells

Abstract

Background. A growing number of hepatocellular carcinoma (HCC), and recurrence frequency recently have drawn researchers’ attention to alternative approaches. The concept of differentiation therapies (DT) relies on inducing differentiation in HCC cells in order to inhibit recurrence and metastasis. Hepatocyte nuclear factor 4 alpha (HNF4α) is the key hepatogenesis transcription factor and its upregulation may decrease the invasiveness of cancerous cells by suppressing epithelial-mesenchymal transition (EMT). This study aimed to evaluate the effect of conjugated linoleic acid (CLA) treatment, natural ligand of HNF4α, on the proliferation, migration, and invasion capacities of HCC cells in vitro. Materials and Method. Sk-Hep-1 and Hep-3B cells were treated with different doses of CLA or BIM5078 [1-(2 ′ -chloro-5 ′ -nitrobenzenesulfonyl)−2-methylbenzimidazole], an HNF4α antagonist. The expression levels of HNF4a and EMT related genes were evaluated and associated to hepatocytic functionalities, migration, and colony formation capacities, as well as to viability and proliferation rate of HCC cells. Results. In both HCC lines, CLA treatment induced HNF4α expression in parallel to significantly decreased EMT marker levels, migration, colony formation capacity, and proliferation rate, whereas BIM5078 treatment resulted in the opposite effects. Moreover, CLA supplementation also upregulated ALB, ZO1, and HNF4α proteins as well as glycogen storage capacity in the treated HCC cells. Conclusion. CLA treatment can induce a remarkable hepatocytic differentiation in HCC cells and attenuates cancerous features. This could be as a result of HNF4a induction and EMT inhibition.

HNF4α is possibly the missing link between epithelial–mesenchymal transition and Warburg effect during hepatocarcinogenesis

“…62 Moreover, Miri-Lavasani et al reported that the treatment of HCC cells using conjugated linoleic acid, as a natural ligand of HNF4α, decreased EMT marker level, migration, and proliferation capacities. 63 Taken together, this study provided a comprehensive and integrated insight into the importance of HNF4α protein in linking several key modules involved in HCC and proposed it as a potential therapeutic target. We revealed that overexpression of HNF4α protein by a synthetic AS lncRNA in the physiological range could simultaneously modulate aberrant changes in metabolism and cellular behavior.…”

“…HNF4α is a tumor suppressor factor, Cheng et al demonstrated that the combination of HNF1A , HNF4A , and FOXA3 synergistically reprograms HCC cells to hepatocyte‐like cells, in which the malignant phenotype is reduced, and hepatocyte‐specific characteristics retrieved 62 . Moreover, Miri‐Lavasani et al reported that the treatment of HCC cells using conjugated linoleic acid, as a natural ligand of HNF4α, decreased EMT marker level, migration, and proliferation capacities 63 …”

“… 62 Moreover, Miri‐Lavasani et al reported that the treatment of HCC cells using conjugated linoleic acid, as a natural ligand of HNF4α, decreased EMT marker level, migration, and proliferation capacities. 63 …”