Docosahexaenoic acid may inhibit immune evasion of colorectal cancer cells through targeting immune checkpoint and immunomodulator genes and their controlling microRNAs

Abstract

Colorectal cancer is one of the major concerns in both developed and developing societies. Because of the serious side effects of the current treatments, novel therapy agents have been developed that target immune checkpoint and immunomodulatory molecules in the tumor environment. Therefore, this study investigates the effect of docosahexaenoic acid (DHA) fatty acid on the expression of immune checkpoint molecule, PD‐L1, and immunomodulatory molecules, CD47 and CD39, and their controlling miRNAs in the colorectal cancer cell lines. Human colorectal cell lines HT‐29 and Caco‐2 were treated with 100 μM DHA and 50 μM LA for 24 h under the normoxic and hypoxic conditions. Total RNA was extracted and the qRT‐PCR was performed to analyze the expression of the studied genes and miRNAs. The western blotting technique was also used for validation. The qRT‐PCR results showed that DHA treatment decreased the expression of the PD‐L1, CD47, and CD39 genes, but decreases these genes controlling miRNAs, mir‐424, mir‐133a, and mir‐142, respectively. Western blotting analysis demonstrated that PD‐L1 protein expression decreased after DHA treatment. LA administration had no inhibitory effect on the studied genes. This study showed that DHA may have anti‐cancer properties by downregulation of proteins involved in the immune evasion of colorectal tumors. DHA could be used as a potential immune checkpoint inhibitor for the treatment of colorectal cancers.

Docosahexaenoic Acid (DHA) Down-regulates Cellular, and Exosomal Overexpressed Mammalian Target of Rapamycin (mTOR) in Breast Cancer Cells Under Hypoxic Condition

“…28 In addition, DHA caused an increase of PTEN in mRNA and protein level of expression so the phosphorylation of the p65 subunit of NF-kB was restrained and VEGF expression was reduced in MDA MB-231 cells. 28 Anti-immunosuppressive effect of DHA has been reported by Fadaee et al 29 In his analysis, DHA suppressed the level expression of immune checkpoint molecules in both normoxic and hypoxic conditions in colorectal cancer cells. 29 Furthermore, lipid deregulation, cell cycle impairment, and oxidative stress were other effects of DHA.…”

“…28 Anti-immunosuppressive effect of DHA has been reported by Fadaee et al 29 In his analysis, DHA suppressed the level expression of immune checkpoint molecules in both normoxic and hypoxic conditions in colorectal cancer cells. 29 Furthermore, lipid deregulation, cell cycle impairment, and oxidative stress were other effects of DHA. 24 The inverse correlation between mTOR expression and miR-101 and miR-214 expression has been validated in several types of human carcinomas.…”

Docosahexaenoic acid (DHA) impairs hypoxia-induced cellular and exosomal overexpression of immune-checkpoints and immunomodulatory molecules in different subtypes of breast cancer cells

“…According to researches, a negative correlation has been discovered between the survival rate of sufferers from BC and the expression of PD-L1 [ 42 ]. Fadaee et al showed that DHA caused down-regulating the expression of PD-L1 in protein level in human colorectal cancer cell lines [ 43 ]. Also, Zhang et al reported that DHA decreased the expression of PD-L1 in lung cancer by rising degradation of ubiquitin-proteasome in vitro and in vivo [ 44 ].…”