美國麻省理工大學伍斯特理工學院Robert E. Dempski教授在自然出版社與川大華西醫院生物治療國家重點實驗室聯合主辦的《Signal Transduction and Targeted Therapy》（STTT）上發表了綜述，討論鋅轉運蛋白在細胞內穩態和在癌癥中的作用。該文的通訊作者為Robert E. Dempski教授，第一作者為Elizabeth Bafaro博士。
Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous protein phosphatase 2A (PP2A) inhibitor, has been identified as an oncoprotein in promoting cancer initiation and progression of several types of cancer. However, the expression and the role played by CIP2A in the pathogenesis of multiple myeloma (MM) remain unclear. In this study, we showed that CIP2A was overexpressed in human MM cell lines and MM patients’ bone marrow tissues. Clinicopathologic analysis showed that CIP2A expression was significantly correlated with clinical stage and percent of plasma cells in bone marrow. Kaplan–Meier analysis revealed that patients with high CIP2A expression presented with poorer overall survival rates than those with low CIP2A expression. Moreover, CIP2A knockdown in MM cells resulted in attenuated proliferative abilities. In addition, CIP2A depletion sensitizes dexamethasone (Dex)-resistant cells to Dex. The effect of CIP2A on proliferation and Dex therapy was mediated by the inhibition of PP2A, which in turn activated Akt. In vivo studies confirmed that CIP2A regulated MM tumorigenesis and the phosphorylation of Akt. Taken together, our results suggest that CIP2A oncoprotein plays an important role in MM progression and could serve as a prognosis marker and a novel therapeutic target for the treatment of patients with MM.
Retroviruses have helped shape the evolution of gene regulation, as highlighted by the mouse VL30-1 RNA that probably arose from a retrovirus infection. In a review article, Alan Garen from Yale University discusses the regulatory properties of VL30-1 RNA that control the expression of multiple genes, including those involved in cell proliferation and cancer. VL30-1 forms a complex with a tumor-suppressor protein called PSF that keeps tumor growth in check, inactivating PSF and promoting cell proliferation and cancer. VL30-1 RNA may have derived from a harmful genomic invader, but over evolutionary time it has co-opted the function of an endogenous regulatory RNA and become indispensable for normal mouse development and survival. Other RNAs that have a similar regulatory function as VL30-1 RNA exist in human cell.
Chemical agents that bind and reversibly modifyspecific DNA sequences could provide the foundation for safer anticancertreatments. Seeing that many current chemotherapy agents kill cancer cells byintroducing irreversible modifications at any site in the genome—damagingnon-target cells while also depleting the amount of drug available to fightcancer—Steven Rokita at the University of Maryland, along with colleagues inChina, sought a more selective and safer approach to treatment. They combinedDNA-modifying compounds known as quinone methides with nucleic acid constructsthat specifically bind particular gene sequences, allowing for targetedtreatment. Importantly, these chemical modifications are potentiallyreversible, minimizing the damage that occurs if the quinone methide-nucleicacid conjugates briefly bind the wrong DNA sequence. This could open doors forthe development of less toxic, targeted chemotherapies that are effective atlower doses
A protein involved in transporting proteins and RNAs out of the cell nucleus offers an attractive target for treating cancer. In a review article, a team led by Qingxiang Sun and Da Jia from Sichuan University, China, discuss the role of the nuclear export factor CRM1 in cancer development. CRM1—which mediates the exit of molecular cargo out of the nucleus and into the cytoplasm—is overexpressed in tumors of the lungs, brain, liver and other organs, and its activity is associated with poor patient outcomes. Drugs that block CRM1 have been tested in clinical trials, with middling success. The authors outline a strategy for a new kind of CRM1 inhibitor that should produce fewer side effects and be less prone to drug resistance than existing agents.
Research elucidating how a protein suppresses the progression of liver cancer could provide new therapeutic targets, say researchers in China. A team led by Rong Xiang and Na Luo at Nankai University examined liver biopsies of patients with hepatocellular carcinoma (HCC), the third most common cause of cancer-related death worldwide. They also grafted HCC cells under the skin of mice. They found that a protein, called TIFA, suppresses the progression of HCC via one of three pathways. One involves competition with another protein, MALT1, to bind with the protein TRAF6, signaling pathways that induce cancer cell death. TIFA-induced cell death also results from suppressing MALT1. Finally, TIFA expression can also activate two genes, JNK and p38, which signal cell death and cell cycle arrest, respectively. The research may provide insights into drug targets that could affect HCC progression.
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