Ren's team reveals important mechanisms for prostate cancer metastasis and immunosuppression

treatment of metastatic desopathic prostate cancer (mCRPC) is a worldwide problem, with very limited survival times (the medium survival time is less than 2 years). Immunotherapy is a hot spot in the field of tumor therapy, as the most promising PD-1/PD-L1 inhibitor in this field, it has encountered challenges in the treatment of prostate cancer, which is still difficult to succeed. Therefore, how to make "cold" tumors such as prostate cancer, which have no strong response to immunotherapy, "hot", so as to improve the effect of tumor immunotherapy represented by PD-1/PD-L1 inhibitors, or to enhance immunotherapy through the discovery of new therapeutic targets and the use of combined drugs will be one of the directions of future treatment of advanced adenocarcinoma.
, on the other hand, long-chain non-coded RNA (lncRNA) has been shown to be involved in the development of prostate cancer by promoting tumor cell proliferation, invasion, metastasis and resistance. As more and more tumor-related lncRNAs are discovered through large samples of RNA sequencing, revealing their involvement in the molecular mechanisms of tumors can help develop lncRNA and its downstream signaling pathstreams as molecular markers or therapeutic targets.
recently, a team of professors at Changhai Hospital of naval medical university, Ren Shancheng, published a research paper online in the journal Molecular Therapy entitled "Novel long non-coding RNA lncAMPC promotes metastasis and immunosuppression in prostate cancer by external lif/LIFR expression". Based on the clinical problems faced by immunotherapy, this study reveals that the long-chain non-coding RNA lncAMPC related to prostate cancer metastasis provides a new strategy and basis for improving the effect of immunotherapy of prostate cancer by regulating the LIF/LIFR signaling path, on the one hand, promoting the distant metastasis of prostate cancer on the other hand.
the long-chain non-coding RNA lncAMPC reported in this paper was obtained by Professor Ren Shancheng's team in a previous study through a transcriptional group sequencing screening of 65 pairs of Chinese prostate cancer and its cancerous tissues (Ren et al. Eur Urol 2018.)。 The researchers found that lncAMPC's expression in both tissue and urine samples in patients with metastatic prostate cancer was significantly higher than in non-metastatic samples, and that liF/LIFR molecules activated by lncAMPC were closely related to the survival of postoperative patients with prostate cancer and had potential value as a molecular marker for prognostic development of prostate cancer.
subsequent in vitro functional experiments confirmed that lncAMPC has the ability to promote the progression and metastasis of prostate cancer. Molecular mechanism studies further found that lncAMPC plays a competitive endogenous RNA (ceRNA) role in prostate cancer cell cytoste, enhancing the role of LIF by competitively binding miR-637 with leukemia inhibitors (LIF) and inhibiting its activity. At the same time, lncAMPC is able to bind histone (Histone) H1.2 in the cytokernels of prostate cancer cells and cause it to dissociate from the upstream sequence of the leukemia inhibitor subject (LIFR) transcription starting point, thereby facilitating the transcription of LIFR. Therefore, lncAMPC, which is highly expressed in metastatic prostate cancer, promotes tumor metastasis by regulating the LIF/LIFR/Jak1/STAT3 pathline, directly activating the expression of downstream-related genes, and suppressing tumor immune response by enhancing the stability of PD-L1.The
team further found that LIF's small molecular inhibitor EC330 significantly inhibited the growth of prostate cancer tumors and PD-L1-mediated tumor immunosuppression, while the most inverted EC330 inhibition of tumors was achieved with CD8 mAb treatment. The findings are expected to improve the effectiveness of immuno-checkpoint inhibitors in prostate cancer treatment for a better clinical response.
(common) first author of this research paper are Zhang Wei, Shi Xiaolei and Chen Rui, and the correspondent is Professor Ren Shancheng. The study was supported by the National Key Research and Development Program (2017YFC0908002), the Shanghai "Top Priority" Clinical Medical Center for Urological Diseases project and the National Natural Science Foundation (81802581,81872105). (Source: Science Network)
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