Lauric acid can improve the sensitization of Cetuximab in KRAS/BRAF mutated colorectal cancer cells by retrievable microRNA-378 expression

Abstract

EGFR-inhibitor (Cetuximab) is one of the main targeted drugs used for metastatic colorectal carcinoma (CRC). The benefit from Cetuximab appears to be limited to a subtype of patients, not for the patients with tumors harboring mutated BRAF or KRAS genes; unfortunately, it accounts for ~40-50% of CRC cases. Previous studies have connected higher expression levels of miR-378 to be commonly presented in patients without BRAF or KRAS mutants than in mutated CRCs. The microRNA-378 (miR-378) is coexpressed with PGC-1β and can be easily induced by fatty acid, for example lauric acid. Therefore, we hypothesized that elevation of miR-378 expression in mutated CRCs may stimulate the cell response to Cetuximab. Herein, seven CRC cell lines with confirmed mutation status were involved in two parallel experiments; directly in vitro transfected miR-378 mimics, and using lauric acid to indirectly induce the level of miR-378 in cells. After the increase of miR-378 in cells by either direct or indirect approaches, sensitivity to Cetuximab was restored in all BRAF mutants (p-value <0.0001-0.0003), and half of KRAS mutants CRC (p-value 0.039-0.007). Further evidence was gained by decreasing expression of MEK and ERK2 proteins after transfection with miR-378; it was similar to the indirect induction by lauric acid approach. In conclusion, the present study demonstrated that lauric acid may efficiently induce miR-378 expression in CRC mutants, and both BRAF and a subtype of KRAS mutants presented significantly improved sensitivity to Cetuximab. Notably, BRAF mutants could even be inhibited in cell proliferation after elevated concentration of miR-378 in cells without combining with targeted therapy. This new approach may shed new light on BRAF or KRAS mutation in CRC patients for clinical trial, since lauric acid may easily be obtain from natural food, and it is supposed to be harmless to the cardiovascular system.

Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter

“…Unfortunately, very few CRC cell lines have been reported to be responsive to EGFR antagonists in vitro. 44 Among the four cell lines with high levels of endogenous EREG expression and EGFR phosphorylation, we chose SW48 as a control because it was the only sensitive line to treatment with EGFR inhibitors 44 (Figure 5d and Supplementary Figure S7b). We also selected cell line CL11 because it exhibited phospho-EGFR induction after 5-aza-dC treatment, which was comparable to the levels observed in SW48 cells.…”

Acute resistance exercise modulates microRNA expression profiles: Combined tissue and circulatory targeted analyses

“…miR-378b which was reduced at 2hr, yet approached basal levels by 4hr post-exercise. miR-378 in cancer and cardiomyocyte models inhibit mitogen activated protein kinases (MAPK), p38 MAPK and ERK1/2 kinase signalling [ 63 , 64 ]. These stress-related pathways have been reported to be activated by physical activity, with peak activity typically evident in the first few hours of exercise recovery [ 65 – 68 ].…”

Tianfoshen oral liquid: a CFDA approved clinical traditional Chinese medicine, normalizes major cellular pathways disordered during colorectal carcinogenesis

“…For example, β-sitosterol that was present in seven of the eight herbs ( Fructus Citri Sarcodactylis being the exception) had demonstrated strong anti-inflammatory, antioxidant and anti-cancer activities [15–17]. Similar pharmacological properties of ursolic acid, quercetin, epicatechin and lauric acid that were present in Radix Asparagi , Radix Actinidia chinensis Planch, Fructus Hippophae and Fructus Citri Sarcodactylis , respectively, had also been demonstrated [18–21]. …”