Robinson Alyncia D, Chakravarthi Balabhadrapatruni V S K, Agarwal Sumit, Chandrashekar Darshan Shimoga, Davenport Mackenzie L, Chen Guoan, Manne Upender, Beer David G, Edmonds Mick D, Varambally Sooryanarayana
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
Transl Oncol. 2021 Aug;14(8):101128. doi: 10.1016/j.tranon.2021.101128. Epub 2021 May 25.
Lung cancer is the leading cause of cancer-related deaths globally and is histologically defined as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), with the latter accounting for 80% of all lung cancers. The 5-year overall survival rate for lung cancer patients is low as it is often discovered at advanced stages when potential cure by surgical resection is no longer an option. To identify a biomarker and target for lung cancer, we performed analysis of multiple datasets of lung cancer gene expression data. Our analyses indicated that the collagen-modifying enzyme Prolyl 4-Hydroxylase Subunit Alpha 1 (P4HA1) is overexpressed in NSCLC. Furthermore, our investigation found that overexpression of enzymes involved in this pathway predicts poor outcome for patients with lung adenocarcinoma. Our functional studies using knockdown strategies in lung cancer cell lines in vitro indicated that P4HA1 is critical for lung cancer growth, migration, and invasion. Additionally, diethyl pythiDC (PythiDC), a small molecule inhibitor, decreased the malignant phenotypes of lung cancer cells. Moreover, we found that miR-124 regulates and targets P4HA1 in lung cancer cells. Thus, our study suggests that collagen-modifying enzymes play an important role in lung cancer aggressiveness. Furthermore, our studies showed that P4HA1 is required for lung cancer cell growth and invasion, suggesting its potential as a valid therapeutic target in lung adenocarcinoma.
肺癌是全球癌症相关死亡的主要原因，在组织学上被定义为小细胞肺癌（SCLC）或非小细胞肺癌（NSCLC），后者占所有肺癌的80%。肺癌患者的5年总生存率较低，因为肺癌通常在晚期才被发现，此时手术切除已无法实现潜在治愈。为了确定肺癌的生物标志物和靶点，我们对多个肺癌基因表达数据集进行了分析。我们的分析表明，胶原蛋白修饰酶脯氨酰4-羟化酶亚基α1（P4HA1）在非小细胞肺癌中过表达。此外，我们的研究发现，参与该途径的酶的过表达预示着肺腺癌患者的预后不良。我们在体外肺癌细胞系中使用敲低策略进行的功能研究表明，P4HA1对肺癌的生长、迁移和侵袭至关重要。此外，小分子抑制剂二乙基硫代二氯（PythiDC）可降低肺癌细胞的恶性表型。此外，我们发现miR-124在肺癌细胞中调节并靶向P4HA1。因此，我们的研究表明，胶原蛋白修饰酶在肺癌侵袭性中起重要作用。此外，我们的研究表明，P4HA1是肺癌细胞生长和侵袭所必需的，这表明它有潜力成为肺腺癌的有效治疗靶点。
