dc.description.abstract | Neuroblastoma (NB), the most common extracranial childhood solid tumor and most common cancer in children younger than one year of age, is arising from neural crest cells of sympathetic nervous system. The clinical outcome of neuroblastoma patients present very high heterogeneity, ranging from spontaneous regression to rapid progression and metastasis. MYCN amplification in neuroblastoma is an unfavorable prognosis marker, and the tumors are highly malignant which often occurs to metastasis and hard to be cured.
Lin28a and Lin28b are RNA-binding proteins, sharing similar amino acid sequence and function, Lin28a and Lin28b inhibit the maturation process of the microRNA family of tumor suppressor, Let-7, and subsequently hinder the inhibition of Let-7 targets. Lin28a/b can also to target mRNAs and promote their translational efficiency. Previous studies showed that Lin28a is highly conserved from C. elegans to mouse, and plays an important role in development. Lin28a is highly express in early stage of nervous system development, but be inhibited during neuronal differentiation. Lin28a/b are found highly expressed in embryonic stem cells, and were used in reprogramming cell to induce pluripotent stem cell (iPS cell). Recently, Lin28a and Lin28b are found to be expressed in various types of human cancers, and their expression was associated with advanced disease stage and poor prognosis. In neuroblastoma, MYCN was known to up-regulate Lin28b expression, and we speculated that Lin28b may participate in pathological mechanism by MYCN-drived neuroblastoma.
A positive correlation between the expression of Lin28b and MYCN that found in our screening of 38 neuroblastoma samples collected in National Taiwan University Hospital, and was confirmed in neuroblastoma data acquired from open resource databases, however, Lin28a expression is not found correlated to expression of MYCN. Higher expression of Lin28b was marginally associated with poor prognosis in those patients with age-of-onset older than 1.5 years. Tumors developed from TH-MYCN transgenic mouse, also present high expression of Lin28b. All these results suggest that Lin28b could be up-regulated by MYCN, and play an oncogenic role in MYCN-driven neuroblastoma. Neuroblastoma cell lines, SK-N-DZ and SK-N-BE are MYCN-amplified and express high level of Lin28b. Knocking down Lin28b expression by lentiviral-delivered shRNAs results in morphological changes, the cell proliferation inhibition, and cell cycle arresting at G0/G1 phase. Moreover, Nestin and MYCN are down-regulated, which suggest that cells are skewing to neuronal differentiation. Reduced anchorage-independent cell growth and matrigel invasion also indicate that Lin28b reduction attenuates malignant characteristics of the cells. Overexpressing Lin28b in SK-N-SH cell line, conversely, upregulates Nestin and MYCN, which suggests that the ectopic expression of Lin28b promote cell de-differentiation and may enhance malignancy. These results indicate that Lin28b is an oncogene in neuroblastoma, and may have a role in promoting MYCN-amplified neuroblastoma. Of notice, our findings also point out that Lin28b up-regulates MYCN or regulates other gene expression to promote malignancy in non-MYCN-amplified neuroblastoma cells. Accordingly, Lin28b can be a new therapeutic target in neuroblastoma. | en |