Research Article: A CREB1/miR-433 reciprocal feedback loop modulates proliferation and metastasis in colorectal cancer

Date Published: December 06, 2018

Publisher: Impact Journals

Author(s): Li Yan, Wei-Qiang You, Neng-Quan Sheng, Jian-Feng Gong, Lan-Dian Hu, Ge-Wen Tan, Hong-Qi Chen, Zhi-Gang Wang.


Increasing evidence has indicated the prognostic value of miR-433 across a series of malignancy types. However, the underlying mechanisms involved in cancer progression haven’t been sufficiently elucidated. In the present work, we found that miR-433 was downregulated in CRC tissues and cell lines. Ectopic expression of miR-433 obviously suppressed the proliferation, invasion and metastasis activity of CRC cells in vitro and in vivo. CREB1, CCAR1 and JNK1 were highly expressed and negatively correlated with miR-433 expression in CRC. CRC patients with higher expression of CREB1, CCAR1 or JNK1 presented a worse outcome relative to those with lower expression. CREB1 transactivated the expression of miR-433, and CREB1, CCAR1 and JNK1 simultaneously served as its targets, which in turn composed a feedback loop between CREB1 and miR-433. miR-433 blocked cell cycle progression and abolished EMT. Collectively, our study demonstrated the CREB1/miR-433 reciprocal feedback loop restrained the propagation, invasion and metastasis activities of CRC cells through abrogation of cell cycle progression and constraint of EMT.

Partial Text

Colorectal cancer (CRC) is one of the most common malignancies worldwide in morbidity and mortality [1–3]. With the comprehensive development of surgery aligned with chemoradiotherapy, molecular targeted agents and immunotherapy, the five-year overall survival (OS) of CRC patients has achieved a superior outcome in the past few decades. However, almost one half of patients will inevitably progress to liver metastasis disease, synchronously or metachronously [4,5]. Upon metastasis, the five-year OS rate does not exceed 10% [6], which is so unsatisfactory for patients and physicians. Even though, unfortunately, most of stage IV patients who successfully receive radical hepatectomy will unavoidably relapse due to chemoresistance. Given the treatment dilemma, it’s urgent to illuminate the mechanisms involved in chemoresistance and to discover some novel predictive biomarkers and molecular reagents.

Although some studies have indicated the prognostic value of miR-433 among several types of malignancies, the mechanisms underlying its involvement in cancer metastasis and recurrence seem to be controversial. On the one hand, Gotanda and colleagues reported that miR-433 increased sensitivity to 5-FU in HeLa cells by regulating of thymidylate synthase [19]. However, Yu et al. and Weiner-Gorzel et al. respectively demonstrated that miR-433 could promote resistance to gemcitabine or paclitaxel in gallbladder and ovarian cancer cells [20,21]. On the other hand, Lin and colleagues observed that miR-433 suppressed hematopoietic cell differentiation in myeloproliferative neoplasms [22]. However, Tang et al. reported that miR-433 could promote osteoblast differentiation [23]. The heterogeneity of cancer could be one reason accounting for the disparity. In addition, given the fact that multiple targets co-exists for a single miRNA, it’s important to uncover and mine the driver targets involved in cancer progression. In this study, we conducted KEGG analyses in the miRWalk database and found that miR-433 was correlative with the MAPK and cAMP signaling pathways and cell adhesion molecules in colorectal cancer. In light of that JNK1 and CREB1 both are key mediator in the MAPK and cAMP signaling pathways, CCAR1 is viewed as a coactivator of β-catenin, we next explored the association between CREB1, CCAR1, JNK1 and miR-433.

In sum, we report the presence of a reciprocal feedback loop between CREB1 and miR-433. miR-433 suppresses CRC proliferation, invasion and metastasis in vitro and in vivo through inhibition of cell cycle progression and EMT by targeting CREB1, CCAR1 and JNK1.




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