Murugan Nirosha J, Voutsadakis Ioannis A
Department of Biology, Algoma University, Sault Sainte Marie P6A3T6, ON, Canada.
Department of Medical Oncology, Sault Area Hospital, Sault Sainte Marie P6A3T6, ON, Canada.
World J Gastrointest Oncol. 2022 Jan 15;14(1):38-54. doi: 10.4251/wjgo.v14.i1.38.
Pancreatic adenocarcinoma is one of the most lethal cancers with rising incidence. Despite progress in its treatment, with the introduction of more effective chemotherapy regimens in the last decade, prognosis of metastatic disease remains inferior to other cancers with long term survival being the exception. Molecular characterization of pancreatic cancer has elucidated the landscape of the disease and has revealed common lesions that contribute to pancreatic carcinogenesis. Regulation of proteostasis is critical in cancers due to increased protein turnover required to support the intense metabolism of cancer cells. The proteasome is an integral part of this regulation and is regulated, in its turn, by key transcription factors, which induce transcription of proteasome structural units. These include FOXO family transcription factors, NFE2L2, hHSF1 and hHSF2, and NF-Y. Networks that encompass proteasome regulators and transduction pathways dysregulated in pancreatic cancer such as the KRAS/ BRAF/MAPK and the Transforming growth factor beta/SMAD pathway contribute to pancreatic cancer progression. This review discusses the proteasome and its transcription factors within the pancreatic cancer cellular micro-environment. We also consider the role of stemness in carcinogenesis and the use of proteasome inhibitors as therapeutic agents.
胰腺腺癌是发病率不断上升的最致命癌症之一。尽管在治疗方面取得了进展，在过去十年中引入了更有效的化疗方案，但转移性疾病的预后仍然比其他癌症差，长期生存只是个例外。胰腺癌的分子特征阐明了该疾病的全貌，并揭示了导致胰腺癌发生的常见病变。由于支持癌细胞强烈代谢所需的蛋白质周转增加，蛋白质稳态的调节在癌症中至关重要。蛋白酶体是这种调节的一个组成部分，反过来又受到关键转录因子的调节，这些转录因子诱导蛋白酶体结构单元的转录。这些转录因子包括FOXO家族转录因子、NFE2L2、hHSF1和hHSF2以及NF-Y。包含蛋白酶体调节因子和在胰腺癌中失调的转导途径（如KRAS/BRAF/MAPK和转化生长因子β/SMAD途径）的网络有助于胰腺癌的进展。本综述讨论了胰腺癌细胞微环境中的蛋白酶体及其转录因子。我们还考虑了干性在致癌作用中的作用以及蛋白酶体抑制剂作为治疗药物的应用。
