Crosstalk between PD-L1 and Jak2-Stat3/ MAPK-AP1 signaling promotes oral cancer progression, invasion and therapy resistance

Arpita Jha; Manzar Alam; Tanushree Kashyap; Nidhi Nath; Anjali Kumari; Kamdeo K Pramanik; Siddavaram Nagini; Rajakishore Mishra

doi:10.1016/j.intimp.2023.110894

Crosstalk between PD-L1 and Jak2-Stat3/ MAPK-AP1 signaling promotes oral cancer progression, invasion and therapy resistance

Int Immunopharmacol. 2023 Nov;124(Pt A):110894. doi: 10.1016/j.intimp.2023.110894. Epub 2023 Sep 6.

Authors

Arpita Jha¹, Manzar Alam¹, Tanushree Kashyap¹, Nidhi Nath¹, Anjali Kumari¹, Kamdeo K Pramanik¹, Siddavaram Nagini², Rajakishore Mishra³

Affiliations

¹ Department of Life Sciences, School of Natural Sciences, Central University of Jharkhand, Cheri-Manatu, Kanke, Ranchi 835 222, Jharkhand, India.
² Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India.
³ Department of Life Sciences, School of Natural Sciences, Central University of Jharkhand, Cheri-Manatu, Kanke, Ranchi 835 222, Jharkhand, India. Electronic address: rajakishore.mishra@cuj.ac.in.

PMID: 37678027
DOI: 10.1016/j.intimp.2023.110894

Abstract

Background: Programmed cell death ligand-1 (PD-L1)is an antitumor immunity molecule and a great target to cure oral cancer; nonetheless, the limited success can be attributed to many complex pathways and tumor-related interferences.

Methods: In the present study, 150 human oral squamous cell carcinoma (OSCC) tissue samples, including 17 adjacent normals, 56 primary tumors, 47 invasive tumors, and 30 therapy-resistant (RT) samples, were included. The parental/cisplatin-resistant (CisR-SCC4/9) cells were utilized for overexpression (Jak1-3 wild type and catalytically inactive), knockdown (PD-L1 siRNA), targeting MAPK/PI3K/Jak-Stat pathways (SMIs) and checking microsomes. The expression of PD-L1, transcription factors (TFs), signaling pathways, survival/apoptosis, therapy resistance, and invasiveness-related molecules/their activity were determined by RT-PCR, Immunohistochemistry, Western blot, Gelatin Zymography, and MTT assay.

Results: Advanced OSCC tumors (invasive and drug-resistance), CisR-SCC4/9 cells, and secretory exosomes (CisR-SCC4/9) were found with increased PD-L1 expression. PD-L1 mRNA/protein showed a positive correlation with different TFs (AP1 > Stat3 > c-myc > NFκB) in tumor samples. The PD-L1 expression was more influenced by Jak-Stat/ MAPK-AP1 pathways over PI3K. The ectopic expression of Jak1-3 suggests Jak2 inducted PD-L1 level over Jak1/Jak3. Finally, PD-L1 directly supports survival (Bcl-xL, Bax, cleaved caspase-3), invasion (MMP2/9), and drug-resistance (ALDH-1A1/-3A1) program in OSCC through its link with several molecules.

Conclusions: PD-L1 was regulated mainly by the Jak2-Stat3/ MAPK-AP1 pathway, and besides the routine immunological functions, it supports OSCC survival, invasion, and therapy resistance. PD-L1 can be used as an indicator of severity and can be targeted along with Jak2-Stat3/ MAPK-AP1 for a better outcome OSCC.

Keywords: Drug-resistance; Invasiveness; Jak2-Stat3; MAPK-AP1; MMP2/9; Oral cancer; PD-L1; Transcription factor.