Identification and Functional Validation of PTH2R as a Therapeutic Target in Lung Adenocarcinoma

Published on Monday, 20 April 2026

Abstract

Background: One of the main causes of cancer-related mortality globally is lung adenocarcinoma (LUAD), necessitating the development of novel therapeutic targets. The parathyroid hormone type 2 receptor (PTH2R) exhibits differential expression across multiple cancers, yet its role in LUAD remains unclear.

Methods: Through an integrated analysis of multiple public databases (including SangerBox 3.0, UALCAN, Kaplan-Meier Plotter, and TIMER), we identified PTH2R-a member of the family B1 GPCRs-as a candidate therapeutic target with significant prognostic value in LUAD. Subsequently, the antitumor effects of PTH2R knockdown and melatonin were evaluated through cell proliferation, colony formation, migration, and apoptosis assays. Transcriptome analysis revealed key biological processes and signaling pathways regulated by PTH2R, identified key genes modulated by PTH2R, and validated core gene expression via RT-qPCR.

Results: PTH2R is a potential therapeutic target for lung adenocarcinoma. Both PTH2R knockdown and melatonin treatment significantly inhibited LUAD cell proliferation, colony formation, and migration capabilities while promoting apoptosis. Notably, the combination of PTH2R knockdown and melatonin treatment demonstrated synergistically enhanced antitumor effects. Transcriptome analysis revealed two key genes within the PTH2R signaling pathway, and RT-qPCR validated the expression of these two key genes.

Conclusions: Our work provides the first evidence confirming the substantial value of PTH2R as a novel therapeutic target for LUAD. It preliminarily demonstrates the mechanism by which melatonin inhibits LUAD by targeting PTH2R, offering crucial experimental evidence and theoretical support for developing precision therapeutic strategies against this cancer.

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The Di Bella's Method: Use of Melatonin and pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea (together with others chemical compounds) in Lung Cancer:

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status;

- Observations on the Report of a case of pulmonary adenocarcinoma with lymph node, hepatic and osseus metastasis;

- The Di Bella Method (A Fixed Part - Melatonin tablets. From 30-40mg/day up to 200mg/day and more orally in patients with advanced stage of cancer disease and/or patients without respond to traditional treatments);

- Melatonin use in cancer patients have started in 1974, when melatonin prepared according to Prof. Di Bella’s formulation [...]. For 11 days was administered to the patient, admitted to the general medical ward at the Maggiore-Pizzardi Hospital in Bologna, very slowly (over approx. 8 hours) and intravenously administered 1000 mg of melatonin for 11 days. During the course of each day, the patient was intravenously administered 4 saline drips of 500 ml, each containing ten 25 mg bottles of freeze-dried melatonin, lasting 2 hours, totaling 1000 mg per day. No other drug of any kind was administered in order to ascertain the effect of the MLT without interference [...]. From Melatonin with adenosine solubilized in water and stabilized with glycine for oncological treatment - technical preparation, effectivity and clinical findings;

- About Melatonin - In vitro, review and in vivo publications;

- Publication: Melatonin anticancer effects: Review (from Di Bella's Foundation);

- Publication: Key aspects of melatonin physiology: 30 years of research (from Di Bella's Foundation);

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- The Di Bella Method (A Fixed Part - Calcium, 2 grams per day, orally);

- The Di Bella Method (A Variable Part - Chondroitin sulfate, up to 3-4 grams per day, orally);

- The Di Bella Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;

- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);

- Publication, 2018 Sep: The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature (from Di Bella's Foundation);

- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);