miR-143 or miR-145 overexpression increases cetuximab-mediated antibody-dependent cellular cytotoxicity in human colon cancer cells

Abstract

miR-143 and miR-145 are downregulated in colon cancer. Here, we tested the effect of restoring these miRNAs on sensitization to cetuximab in mutant KRAS (HCT116 and SW480) and wild-type KRAS (SW48) colon cancer cells. We evaluated cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and the modulation of signaling pathways involved in immune effector cell-mediated elimination of cancer cells. Stable miR-143 or miR-145 overexpression increased cell sensitivity to cetuximab, resulting in a significant increase of cetuximab-mediated ADCC independently of KRAS status. Importantly, HCT116 cells overexpressing these miRNAs triggered apoptosis in result of cetuximab-mediated ADCC, effected by peripheral blood mononuclear cells (p < 0.01). This was associated with increased apoptosis and caspase-3/7 activity, and reduced Bcl-2 protein expression (p < 0.01). In addition, caspase inhibition abrogated cetuximab-mediated ADCC in HCT116 cells overexpressing either miR-143 or miR-145 (p < 0.01). Furthermore, Bcl-2 silencing led to high level of cetuximab-mediated ADCC, compared to control siRNA (p < 0.05). Importantly, granzyme B inhibition, abrogated cetuximab-mediated ADCC, reducing caspase-3/7 activity (p < 0.01). Collectively, our data suggests that re-introduction of miR-143 or miR-145 may provide a new approach for development of therapeutic strategies to re-sensitize colon cancer cells to cetuximab by stimulating cetuximab-dependent ADCC to induce cell death.

The Influence of Spirulina platensis Filtrates on Caco-2 Proliferative Activity and Expression of Apoptosis-Related microRNAs and mRNA

“…The expression of miR-17 and miR-146 was downregulated, while the expression of miR-145 was upregulated. This is consistent with the role of these miRNAs in cancer development—the overexpression of miR-17 and mir-146 is a feature of hyper-proliferating cancer cells [20,59], while the enhanced expression of miR-145 impairs proliferation of the HCT116 colon cancer cell line [60]. …”

Kirsten Ras* oncogene: Significance of its discovery in human cancer research

“…Silencing of KRAS mRNAs using siRNA [124, 125] or miRNAs (such as Let-7 [126] or miR143 [127]), which indirectly suppress levels of mutated KRAS proteins in cancer cells. A new administration method was developed to maintain siRNA stability and to introduce siRNA slowly into KRAS G12D -mutated pancreatic carcinoma tissue [125].…”

Folic acid modulates cancer‐associated micro RNAs and inflammatory mediators in neoplastic and non‐neoplastic colonic cells in a different way

“…The repression of these miRNAs suggest a specific growth promoting overall effect of FA on the malignant cells in our study, because ectopic expression of miR‐1, miR‐126, miR‐139 and miR‐34a was shown to suppress the proliferation of colon and other cancer cells . Furthermore, the ectopic expression of miR‐143 restores the responsiveness of colon cancer cells for the anti‐EGFR antibody cetuximab, which is therapeutically used as anti‐cancer drug .…”