In Hepatocellular Carcinoma miR-221 Modulates Sorafenib Resistance through Inhibition of Caspase-3–Mediated Apoptosis

Abstract

The aberrant expression of miR-221 is a hallmark of human cancers, including hepatocellular carcinoma (HCC), and its involvement in drug resistance, together with a proved efficacy of anti-miR-221 molecules, strengthen its role as an attractive target candidate in the oncologic field. The discovery of biomarkers predicting the response to treatments represents a clinical challenge in the personalized treatment era. This study aimed to investigate the possible role of miR-221 as a circulating biomarker in HCC patients undergoing sorafenib treatment as well as to evaluate its contribution to sorafenib resistance in advanced HCC. A chemically induced HCC rat model and a xenograft mouse model, together with HCC-derived cell lines were employed to analyze miR-221 modulation by Sorafenib treatment. Data from the functional analysis were validated in tissue samples from surgically resected HCCs. The variation of circulating miR-221 levels in relation to Sorafenib treatment were assayed in the animal models and in two independent cohorts of patients with advanced HCC. MiR-221 over-expression was associated with Sorafenib resistance in two HCC animal models and caspase-3 was identified as its target gene, driving miR-221 anti-apoptotic activity following Sorafenib administration. Lower pre-treatment miR-221 serum levels were found in patients subsequently experiencing response to Sorafenib and an increase of circulating miR-221 at the two months assessment was observed in responder patients. MiR-221 might represent a candidate biomarker of likelihood of response to Sorafenib in HCC patients to be tested in future studies. Caspase-3 modulation by miR-221 participates to Sorafenib resistance. .

miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro

“…In conclusion, regarding the results of this manuscript, our previous results and the established role of miR-221 in TKI resistance [7,34] together could offer a promising clinical perspective. Low miR-221 expression in aggressive PCa characterized by VEGFR2 overexpression not only marks patients with a significantly higher risk of progression [12], but those most likely to benefit from anti-angiogenic therapy.…”

MicroRNAs in Animal Models of HCC

“…In the same model, miR-221 overexpression associated with sorafenib resistance and caspase-3 was recognized as its target gene, contributing to miR-221 anti-apoptotic activity and drug-resistant phenotype. Notably, an association between high miR-221 or low caspase-3 levels and tumor multifocality was assessed in human HCC specimens, suggesting the robustness and specificity of preclinical data and their reliability with respect to the human pathology [167].…”

“…The AKT/mTOR pathway is frequently activated in HCC, characterizing a subgroup of patients with a high proliferation signature and sorafenib resistance [179][180][181]. Several miRNAs contribute to its post-transcriptional regulation mediating sorafenib resistance in preclinical models, highlighting its central role in HCC progression and treatment escape [11,15,68,114,167]. Interestingly, the R-H model is also suitable for the investigation of oval cell population, due to its rapid expansion following partial hepatectomy.…”

Development of miRNA‐based therapeutic approaches for cancer patients

“…In HCC, miR-221 induces sorafenib resistance through direct inhibition of caspase 3. 39 More importantly, the expression level of circulating miR-221 in serum is significantly associated with sorafenib resistance in HCC patients. In B-cell lymphoma, miR-377 promotes resistance to ABT199 (venetoclax) by directly targeting B-cell lymphoma-extra large 37.…”