Published online Jul 14, 2022. doi: 10.3748/wjg.v28.i26.3177
Peer-review started: January 13, 2022
First decision: March 8, 2022
Revised: March 21, 2022
Accepted: May 27, 2022
Article in press: May 27, 2022
Published online: July 14, 2022
Processing time: 180 Days and 17.1 Hours
Colorectal cancer (CRC) patients usually relapse and die due to the development of metastasis and resistance to chemotherapeutic drugs employed in the treatment. Parathyroid hormone-related peptide (PTHrP) is a cytokine that has a key role in the carcinogenesis and the progression of several tumors. Our research group found that the binding of PTHrP to its receptor, the parathyroid hormone receptor type 1 (PTHR1), promotes events associated with the aggressive phenotype of colorectal cancer cells. The receptor tyrosine kinase Met is associated with metastasis and chemoresistance in CRC.
The mechanisms that lead to an aggressive tumor behavior and a worse response to CRC treatment are still unknown. To date, it has not been studied whether there is a cross-talk between the PTHrP and Met signaling pathways to trigger molecular mechanisms associated with CRC progression.
To investigate the relationship between PTHR1, PTHrP, and Met in the aggressive behavior of CRC cells. These findings could have implications for the future diagnosis, prognosis, and treatment of patients with CRC.
By RT-PCR and Western blot analysis, we studied whether PTHrP modulates the expression of Met and its activation in CRC cells. By Western blot and using specific inhibitors, we also evaluated the signaling pathways involved in Met activation induced by PTHrP. By Trypan blue technique, Wound healing assay, Western blot, and morphological analysis, we evaluated whether the Met signaling pathway mediates the effects induced by PTHrP in HCT116 cells. By the immunohistochemistry technique, we evaluated the expression of Met and the PTHrP receptor, PTHR1, in HCT116 cell xenografts of nude mice in response to the treatment with or without PTHrP. An observational analysis of human samples was performed to validate the findings obtained by in vitro and in vivo assays.
PTHrP modulated the expression of Met and promoted its activation through Src kinase and the mitogen-activated protein kinase (MAPK) signaling pathway in human HCT116 cells. The Met signaling pathway triggered by PTHrP participated in cellular events related to the aggressive behavior of human HCT116 cells such as proliferation, morphological changes associated with epithelial to mesenchymal transition, and migration and in the decrease of the sensitivity to chemotherapy drugs. PTHrP increased the protein expression of its receptor, PTHR1, and of Met in HCT116 cell tumor xenografts. PTHR1 was highly expressed in well-differentiated human CRC samples. In contrast, Met showed an expression pattern that was increased in poorly differentiated CRC tumors.
PTHrP promotes events associated with a worse behavior of CRC cells through Met activation. To date, our in vitro observations suggest that the binding of PTHrP to its receptor, PTHR1, promotes the regulation of Met gene expression and also its activation through the Src kinase and the MAPKs pathway. Once activated, Met signaling leads to molecular changes in the tumor cell to promote events associated with the aggressive behavior of CRC cells. Our previous data together with the findings shown herein reveal that PTHrP in vivo modulates the expression of markers linked to tumor progression (including Met) and also of its own receptor. These events could favor the tumor phenotype in the CRC animal model studied in this work.
In the future, it will be of great interest to evaluate whether Met mediates other molecular mechanisms and events triggered by PTHrP that are involved in CRC progression. Concerning translational relevance, more studies are needed in the areas of basic and clinical oncology.