Gliomas are associated with high mortality because of their exceedingly invasive character. Since these tumors acquire their invasiveness from low-grade tumors, it is very important to understand the detailed molecular mechanisms of invasion onset. Recent evidences suggest the significant role of microRNAs in tumor invasion. Thus, we hypothesized that deregulation of microRNAs may be important for the malignant progression of gliomas. Here, we found that the aberrant expression of miR-21 is responsible for glioma invasion by disrupting the negative feedback circuit of Ras/MAPK signaling, which is mediated by Spry2. Upregulation of miR-21 was triggered by tumor microenvironmental factors such as hyaluronan and growth factors in glioma cells lacking functional PTEN, but not harboring wild-type PTEN. Consistently with these in vitro results, Spry2 protein levels were significantly decreased in 79.7% of invasive WHO grade II-IV human glioma tissues, but not in non-invasive grade I and normal tissues. The Spry2 protein levels were not correlated with their mRNA levels, but inversely correlated with miR-21 levels. Taken together, these results suggest that the post-transcriptional regulation of Spry2 by miR-21 plays an essential role on the malignant progression of human gliomas. Increased miR-21 and decreased Spry2 shown in most of our human glioma tissues emphasize the therapeutic relevance of miR-21 and Spry2 for the future treatment of gliomas.
As above, aberrant miR-21 expression is closely associated with cell proliferation, anti-apoptosis, migration, invasion, and metastasis in various cancers. However, the regulatory mechanism of miR-21 biogenesis is largely unknown. Here, we demonstrated that the tumor suppressor PTEN negatively regulates the expression of oncogenic miR-21 at the post-transcriptional level. Moreover, our results suggest that PTEN plays such a role through the indirect interaction with the Drosha complex. To elucidate how PTEN regulates pri- to pre-miR-21 processing, we attempted to find PTEN-interacting proteins and identified an RNA-regulatory protein, RNH1. Using the sensor to monitor pri-miR-21 processing, we demonstrated that RNH1 is necessary and sufficient for pri-miR-21 processing. Moreover, our results propose that the nuclear localization of RNH1 is important for this function. Further analysis showed that RNH1 directly interacts with the Drosha complex and that PTEN blocks this interaction. Taken together, these results suggest that the PTEN-mediated miR-21 regulation is achieved by inhibiting the interaction between the Drosha complex and RNH1, revealing the previously unidentified role of PTEN in the oncogenic miR-21 biogenesis.
신경교종은 보통 주위 정상 조직을 침투하여 자라기 때문에 수술로 완전 제거하는 것이 어려워, 대부분의 경우 재발하여 예후가 좋지 않다. 따라서 이러한 침윤의 분자생물학적 기전을 규명하는 것이 향상된 치료법 개발을 위해 대단히 중요하다.
최근 연구에 따르면 마이크로RNA가 암세포의 침윤에 중요한 역할을 한다고 알려져 있다. 이를 바탕으로 본 논문에서는 신경교종의 침윤에서 마이크로RNA의 역할에 대해 연구하였다. 그 결과 마이크로RNA-21(miR-21)이 Spry2 유전자의 발현을 전사 후 조절함으로써 신경교종 세포의 침윤성을 증가시킨다는 것을 규명하였다. 실제 신경교종 환자의 조직 샘플에서도 대부분 정상 조직에 비해 miR-21의 양은 증가, Spry2 단백질의 양은 감소되어 있었다.
다음으로, 이러한 miR-21의 생성이 어떻게 조절되는지에 대해 연구하여, 대표적인 암 억제 유전자인 PTEN이 miR-21의 생성을 전사 후 조절함을 규명하였다. 또한 이것은 PTEN이 RNA 조절 단백질 중 하나인 RNH1과의 결합을 통해 Drosha에 의한 miR-21 가공을 억제함으로써 이루어짐을 밝혀내었다.
이러한 연구 성과들을 통해 그 기능이 새롭게 밝혀진 유전자들은, 향후 신경교종의 치료를 보다 향상시키기 위한 새로운 치료제 개발 시 중요한 치료 표적이 될 수 있을 것이다.
