Abstract
One of the treatment failures for colorectal cancer (CRC) is resistance to chemotherapy drugs. miRNAs have been demonstrated to be a new regulator of pathobiological processes in various tumors. While few studies have explored the specific role of miR-141 in mediating 5-fluorouracil (5-FU) sensitivity of CRC cells, the present study aimed to detect the contribution of miR-141 in 5-FU sensitivity. The CRC cells viability was measured by MTS assay and cell colony forming. The expression of miR-141 and its downstream targets were assessed by reverse transcription quantitative PCR, Western blotting, and immunohistochemistry. The functional assays were conducted using CRC cells and nude mice. At the present study, we found overexpression of miR-141 could inhibit proliferation, migration, tumor-forming and invasive potential of CRC cells in vitro and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was verified as a directed target of miR-141. The combination treatment of miR-141 with 5-FU, directly targetting MAP4K4, could better inhibit invasion and metastasis of CRC cells colony than either one alone. Furthermore, overexpression of miR-141, targetting MAP4K4, enhanced the effected of 5-FU and suppressed the malignant biological behaviors, in vivo. Our findings showed that 5-FU inhibited malignant behavior of human CRC cells in vitro and in vivo by enhancing the efficiency of miR-141. Our data suggested that targetting the miR-141/MAP4K4 signaling pathway could be a potential molecular target that may enhance chemotherapeutic efficacy in the treatment of CRC.
Highlights
In China, colorectal cancer (CRC) is the third and fourth most common high mortality cancer of males and females respectively [1]
We evaluated the effect of miR-141 over expression and low expression on the proliferation of CRC cells
Because of the introduction of the currently used FOLFOX and FOLFIRI regiments in metastatic CRC, the response rates have been improved to about 30–40% [14]; the resistance to chemotherapy is still a major barrier in the CRC treatment
Summary
In China, colorectal cancer (CRC) is the third and fourth most common high mortality cancer of males and females respectively [1]. Surgery including chemotherapy and/or radiotherapy is the most basic treatment method in the stage patients. 25–50% of patients with metastasis CRC miss the optimal treatment opportunity [2]. The effective diagnosis and treatment for CRC are urgent needed. Identifying the molecular target in early diagnosis, therapy and prognosis of cancer have become the focus of anticancer research field. The formation mechanism, prevention, and treatment modality of CRC has not been fully illuminated. Understanding the pathological mechanism of CRC and searching for novel targets for preventing CRC remains to be needed
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