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Growth Hormone Elevates Pro-Tumor Cargoes in Melanoma-Derived Exosomes

Kulkarni, Prateek
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1722440889003943

Abstract Details

2024, Doctor of Philosophy (PhD), Ohio University, Molecular and Cellular Biology (Arts and Sciences).
Growth hormone (GH) is known to play a crucial role in melanoma progression and the development of drug resistance. Recent studies have implicated melanoma-derived exosomes in these processes, although the direct effects of GH on melanoma-derived exosomes remain unexplored. This study aims to investigate the impact of GH in modulating cargoes in melanoma-derived exosomes. Characterization of melanoma-derived exosomes revealed that GH caused changes in exosomal cargo without affecting the morphological features or secretion characteristics of exosomes. We observe that GH elevated multiple mRNAs within exosomes, including stearoyl-CoA desaturase (SCD), potassium channel tetramerization domain 20 (KCTD20), and zinc-finger CCCH-type containing antiviral 1 (ZC3HAV1), which are associated with cancer progression. Concurrently, GH suppressed non-coding RNAs such as mir-98 and mr-185, which are linked to tumor suppression. Inhibition of GH action by pegvisomant reversed these expression patterns. Strikingly, pegvisomant alone elevated various cargoes such as tumor suppressing exosomal lncRNA Growth Arrest Specific transcript (GAS5), indicating independent action of pegvisomant in modulating exosomal cargoes. Previous studies from our lab and others have demonstrated that GH expression exacerbates chemotherapy resistance and cancer invasion in melanoma via upregulating the levels of ATP-binding cassette transporters (ABC) transporters, epithelial to mesenchymal transition (EMT) markers, and matrix metalloproteinases (MMPs). We assessed exosomal ABC transporters, EMT markers, MMPs associated with GH. GH treatment elevated exosomal ABC transporters, specifically ABCC1 and ABCB1, with levels further increasing in the presence of chemotherapy, in particular, doxorubicin. Furthermore, assessing the exosomal transfer of these ABC transporters revealed that GH-induced exosomes elevated the levels of these ABC transporters in recipient cells and resulted in decreased drug retention capacity. Pegvisomant attenuated the exosomal ABC transporters levels and their transfer, resulting in an enhancement of chemosensitivity in recipient cells. Additionally, GH treatment upregulated exosomal N-cadherin and MMP2, while pegvisomant attenuated these. Recipient cells administered with GH-induced exosomes exhibited elevated N-cadherin without changes in MMP2 levels. GH-induced exosomes enhanced migration of recipient melanoma cells, whereas pegvisomant reduced the migration. This indicates that GH-induced exosomes promote melanoma cell migration by providing the recipient cells with elevated N-cadherin that may facilitate mesenchymal transition, while elevated exosomal MMP2 aids in the degradation of extracellular matrix. Overall, we demonstrate that GH promotes pro-tumor coding and non-coding RNAs, as well as critical proteins in melanoma-derived exosomes.
John Kopchick (Advisor)
184 p.
Cellular Biology; Molecular Biology
growth hormone; exosomes; melanoma; chemotherapy resistance; ABC transporters; N-cadherin; MMP2; pegvisomant, SCD, KCTD20, mir-98, mir-185, lncRNA, GAS5

Recommended Citations

Citations

  • Kulkarni, P. (2024). Growth Hormone Elevates Pro-Tumor Cargoes in Melanoma-Derived Exosomes [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1722440889003943

    APA Style (7th edition)

  • Kulkarni, Prateek. Growth Hormone Elevates Pro-Tumor Cargoes in Melanoma-Derived Exosomes. 2024. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1722440889003943.

    MLA Style (8th edition)

  • Kulkarni, Prateek. "Growth Hormone Elevates Pro-Tumor Cargoes in Melanoma-Derived Exosomes." Doctoral dissertation, Ohio University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1722440889003943

    Chicago Manual of Style (17th edition)

ohiou1722440889003943
© 2024, all rights reserved.
This open access ETD is published by Ohio University and OhioLINK.