Beyond Hormones: Investigating the Impact of Progesterone Receptor Membrane Component 1 in Lung Adenocarcinoma.

Progesterone Receptor Membrane Component 1 (PGRMC1) is a candidate oncogene with a prominent involvement in the pathogenesis of diverse cancers (ovarian, thyroid, breast, colon, head, and neck). Our study ascertains the ability of PGRMC1 to influence WNT members in the non-small cell lung cancer subtype-lung adenocarcinoma (LUAD) and participates in augmented cell proliferation and migration. Both computational and in vitro experimental analyses were performed in this study. Gene silencing, in vitro assays, gene expression & and protein expression studies were performed to ascertain the role of PGRMC1 in LUAD cells. The computational analysis, PGRMC1 gene level expression was analysed using the microarray gene expression omnibus datasets (GSE27262; GSE18842) to compare LUAD tumours and normal tissues. Concurrently, the gene expression profiling interactive analysis of PGRMC1 and Kaplan-Meier survival analysis revealed a decreasing patient survival rate with an increasing PGRMC1 gene expression in LUAD tumour samples. Interestingly, the experimental gene silencing studies were conducted in vitro (si-PGRMC1 Vs si-Control) to understand the essential role of PGRMC1 in regulating WNT-associated genes (WNT1, WNT5A, and WNT11). Comparative experimental cell migration and spheroid formation assays (si-PGRMC1 Vs si-Control) in vitro showed a strong association between PGRMC1 and LUAD. In vitro expression analysis using real-time PCR and western blot further confirmed the connecting link between PGRMC1 and WNT5A compared to other WNT member genes (WNT1 and WNT11) in LUAD. The computational and experimental analyses agreed with one another.

Solairaja S ，Venkatabalasubramanian S 《-》

Synaptotagmin 12 (SYT12) Gene Expression Promotes Cell Proliferation and Progression of Lung Adenocarcinoma and Involves the Phosphoinositide 3-Kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) Pathway.

Liu K ，Luo J ，Shao C ，Ren Z ，Sun S ，Zhu Y ，Zhou H ，Jiang Z ，Li X ，Gu W ，Xu Y ，Qiang Y ，Ren B ，Xu L ，Wu H ，Shen Y ... -  《MEDICAL SCIENCE MONITOR》

Elevated progesterone receptor membrane component 1/sigma-2 receptor levels in lung tumors and plasma from lung cancer patients.

Cancer is one of the leading causes of death, and there is an urgent need for new biomarkers and therapeutic targets. The progesterone receptor membrane component 1 (Pgrmc1) protein is upregulated in multiple types of cancer, and Pgrmc1 is required for tumor cell proliferation, motility and tumor formation in vivo. Furthermore, a small molecule inhibitor of Pgrmc1 suppressed the growth of lung, breast and cervical cancer cell lines. Recently, Pgrmc1 was identified as the sigma-2 receptor, a putative type of opioid receptor, and sigma-2 receptors are induced in cancers. However, Pgrmc1 shares no homology with known opioid or hormone receptors but is related to cytochrome b(5), and Pgrmc1 binds to heme and has reducing activity. In this study, we have analyzed Pgrmc1 levels in clinical tumor samples from squamous cell lung cancers (SCLC) and lung adenocarcinomas compared to corresponding nonmalignant tissue. Pgrmc1 levels increased significantly (p ≤ 0.05) in 12/15 SCLC samples and was elevated in poorly differentiated tumors. Pgrmc1 was highly expressed in SCLC cell lines, and SCLC cell survival was inhibited by siRNA knockdown of Pgrmc1 or the Pgrmc1 inhibitor AG-205. In adenocarcinomas, 6/15 tumors significantly had elevated Pgrmc1 levels, which correlated with patient survival. Pgrmc1 localizes to secretory vesicles in cancer cells, and Pgrmc1 was secreted by lung cancer cells. Furthermore, Pgrmc1 was significantly elevated in the plasma of lung cancer patients compared to noncancer patients. Together, the results demonstrate that Pgrmc1 is a potential tumor and serum biomarker, as well as a therapeutic target, for lung cancer.

Mir SU ，Ahmed IS ，Arnold S ，Craven RJ ... -  《-》

Progesterone receptor membrane component 1 leads to erlotinib resistance, initiating crosstalk of Wnt/β-catenin and NF-κB pathways, in lung adenocarcinoma cells.

Lin Y ，Higashisaka K ，Shintani T ，Maki A ，Hanamuro S ，Haga Y ，Maeda S ，Tsujino H ，Nagano K ，Fujio Y ，Tsutsumi Y ... -  《Scientific Reports》

Exploring the effects of pemetrexed on drug resistance mechanisms in human lung adenocarcinoma and its association with PGRMC1.

According to the 2022 cancer statistics of the World Health Organization, lung cancer ranks among the top ten causes of death, with lung adenocarcinoma being the most prevalent type. Despite significant advancements in lung cancer therapeutics, many clinical limitations remain, primarily due to the development of drug resistance. The present study investigated the effects of pemetrexed on the drug resistance mechanisms in human lung adenocarcinoma and its association with progesterone receptor membrane component 1 (PGRMC1) expression. Given that KRAS-mutant lung adenocarcinoma cell lines (e.g., A549) exhibit a high folate synthesis activity, pemetrexed, which is structurally similar to folate, was selected as the therapeutic drug. The present study used a lung adenocarcinoma cell line (A549) and established a drug-resistant lung adenocarcinoma cell line (A549/PEM). The findings demonstrated that PGRMC1 expression was elevated in the A549/PEM cells. It has been hypothesized that PGRMC1 regulates iron absorption through heme binding, resulting in a preference for iron-related cell death pathways (ferroptosis). Our findings indicate that drug-resistant lung adenocarcinoma cells with high PGRMC1 levels exhibit elevated antioxidant activity on the cell membrane and increased reliance on iron-dependent cell death pathways. This suggests a correlation between PGRMC1 and pemetrexed-induced iron-dependent cell death. Our study contributes to the development of more effective therapeutic strategies to improve the prognosis of patients with lung adenocarcinoma, particularly those facing drug resistance challenges.

Wu SY ，Liao EC ，Wen YF ，Wang YS ，Meng H ，Chou HC ，Chan HL ... -  《-》