Wang Wei, Jiang Chun-Fan, Yin Hai-Sen, Gao Shan, Yu Bao-Ping
Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Department of Gastroenterology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021, China.
Department of Pathology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021, China.
Hepatobiliary Pancreat Dis Int. 2023 Oct;22(5):519-527. doi: 10.1016/j.hbpd.2023.03.006. Epub 2023 Mar 21.
The survival of pancreatic cancer cells, particularly cancer stem cells which are responsible for tumor relapse, depends on mitochondrial function. Mitochondrial transcription factor A (TFAM) is critical for the regulation of mitochondrial DNA and thus mitochondrial function. However, the possible involvement of TFAM in pancreatic cancer is unknown.
Human samples were obtained from pancreatic cancers and their adjacent tissues; human pancreatic cell lines were cultured in RPMI1640 medium. TFAM expressions in pancreatic tissues and cultured cells were determined using immunohistochemistry, ELISA, and reverse transcription polymerase chain reaction (RT-PCR). The effect of TFAM on cell growth, migration, colony formation and apoptosis were evaluated. Mitochondrial biogenesis in pancreatic cancer and normal cells were examined.
The majority of pancreatic cancer tissues exhibited higher TFAM expression compared to the adjacent counterparts. Consistently, TFAM mRNA and protein levels were higher in pancreatic cancer cell lines than in immortalized normal pancreatic epithelial cells. There was no difference on TFAM level between gemcitabine-sensitive and resistant pancreatic cancer cells. Functional analysis demonstrated that TFAM overexpression activated pancreatic normal and tumor cells whereas TFAM inhibition effectively inhibited the growth of pancreatic cancer cells. TFAM inhibition enhanced gemcitabine's cytotoxicity and suppressed growth, anchorage-independent colony formation and survival of gemcitabine-resistant pancreatic cancer cells. Mechanistic studies showed that TFAM inhibition resulted in remarkable mitochondrial dysfunction and energy crisis followed by oxidative stress. The basal mitochondrial biogenesis level correlated well with TFAM level in pancreatic cancer cells.
TFAM played essential roles in pancreatic cancer via regulating mitochondrial functions which highlighted the therapeutic value of inhibiting TFAM to overcome gemcitabine resistance.
胰腺癌细胞的存活，尤其是导致肿瘤复发的癌症干细胞，依赖于线粒体功能。线粒体转录因子A（TFAM）对于线粒体DNA的调控以及线粒体功能至关重要。然而，TFAM在胰腺癌中的潜在作用尚不清楚。
从胰腺癌及其相邻组织获取人类样本；人胰腺细胞系在RPMI1640培养基中培养。使用免疫组织化学、酶联免疫吸附测定（ELISA）和逆转录聚合酶链反应（RT-PCR）测定胰腺组织和培养细胞中TFAM的表达。评估TFAM对细胞生长、迁移、集落形成和凋亡的影响。检测胰腺癌和正常细胞中的线粒体生物合成。
与相邻组织相比，大多数胰腺癌组织表现出更高的TFAM表达。同样，胰腺癌细胞系中TFAM的mRNA和蛋白质水平高于永生化的正常胰腺上皮细胞。吉西他滨敏感和耐药的胰腺癌细胞之间的TFAM水平没有差异。功能分析表明，TFAM过表达激活胰腺正常细胞和肿瘤细胞，而抑制TFAM可有效抑制胰腺癌细胞的生长。抑制TFAM增强了吉西他滨的细胞毒性，并抑制了吉西他滨耐药胰腺癌细胞的生长、非锚定依赖性集落形成和存活。机制研究表明，抑制TFAM导致显著的线粒体功能障碍和能量危机，随后产生氧化应激。胰腺癌细胞中的基础线粒体生物合成水平与TFAM水平密切相关。
TFAM通过调节线粒体功能在胰腺癌中发挥重要作用，这突出了抑制TFAM以克服吉西他滨耐药性的治疗价值。
