NDLI: JAK1 inactivation promotes proliferation and migration of endometrial cancer cells via upregulating the hypoxia-inducible factor signaling pathway

Content Provider	Springer Nature : BioMed Central
Author	Lin, Qin Chen, Zheng Shi, Wei Lv, Zeheng Wan, Xiaoping Gao, Kun
Abstract	Background Loss-of-function (LOF) mutations of JAK1, a member of the JAK kinase family, were frequently observed in EC, indicating that JAK1 may act as a tumor suppressor, at least in EC. However, the mechanism of JAK1 mediated regulation of tumorigenesis remains poorly understood. Methods The genetic alterations of JAK1 in EC using latest sequencing dataset of EC deposited in TCGA database. The RNA-Seq dataset of EC and normal endometrial tissues from TCGA cohort was analyzed. The expression of JAK1 in EC and normal endometrial tissues were investigated using immunohistochemistry. The expression levels of genes in endometrial cancer cells were detected by quantitative reverse transcription-PCR (RT-qPCR) and western blotting. JAK1 protein was efficiently depleted by the two shRNAs. HIF1/2-α protein was efficiently depleted by siRNAs. JAK1 overexpressed EC cells were generated by an expressing plasmid. The proliferation and migration ability of cancer cells were evaluated by CCK8, colony formation assays and transwell assays. The global transcriptomic changes in JAK1-depleted KLE cells were investigated using RNA-Seq. Gene Ontology (GO) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were used to identify the most significant pathways that were altered in JAK1-depleted KLE cells. The physical association between HIF-1/2α and JAK1 using co-immunoprecipitation (co-IP) assays. Results In the present study, we found that JAK1 was frequently mutated and downregulated in EC. JAK1 knockdown promotes EC cell proliferation and migration. JAK1 overexpression reduces EC cell proliferation and migration. We examined the transcriptional profiling changes in JAK1-depleted EC cells and unexpectedly found that the hypoxia inducible factor (HIF) pathway was activated. Mechanistically, JAK1 interacts with HIF-1/2α, and reduces HIF1/2-α protein expression under hypoxia. HIF-1/2α knockdown reverses the JAK1 knockdown–induced growth and migration of EC cells under hypoxia. JAK1 knockdown or pharmacological inhibition of JAK1 kinase activity by Ruxolitinib upregulates transcription of HIF target genes under hypoxia. JAK1 overexpression downregulates transcription of HIF target genes under hypoxia. Conclusions These findings provide novel insights into the functional link between JAK1 LOF mutations and abnormal HIF pathway activation in EC and suggest that pharmacological inhibition of HIF1/2 represents a promising therapeutic strategy targeting JAK1-mutated ECs. Video Abstract
Related Links	https://biosignaling.biomedcentral.com/counter/pdf/10.1186/s12964-022-00990-5.pdf
Ending Page	13
Page Count	13
Starting Page	1
File Format	HTM / HTML
DOI	10.1186/s12964-022-00990-5
Journal	Cell Communication and Signaling
Issue Number	1
Volume Number	20
Language	English
Publisher	BioMed Central
Publisher Date	2022-11-14
Access Restriction	Open
Subject Keyword	Cell Biology Protein-Ligand Interactions Receptors Cytokines and Growth Factors Endometrial cancer JAK1 HIF-1α HIF-2α Proliferation Migration
Content Type	Text
Resource Type	Article
Subject	Biochemistry Cell Biology Molecular Biology
Journal Impact Factor	8.2/2023
5-Year Journal Impact Factor	8/2023

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Vitamin D/VDR signaling inhibits LPS-induced IFNγ and IL-1β in Oral epithelia by regulating hypoxia-inducible factor-1α signaling pathway

Hypoxia-inducible factor 2α (HIF-2α) promotes colon cancer growth by potentiating Yes-associated protein 1 (YAP1) activity

Hypoxia-inducible factor (HIF) network: insights from mathematical models

Autocrine motility factor promotes endometrial cancer progression by targeting GPER-1

Correction: Adiponectin affects the migration ability of bone marrow-derived mesenchymal stem cells via the regulation of hypoxia inducible factor 1α

Interaction with ErbB4 Promotes Hypoxia-inducible Factor-1α Signaling

Hypoxia-inducible factor 2α (HIF-2α) promotes colon cancer growth by potentiating Yes-associated protein 1 (YAP1) activity

Adiponectin affects the migration ability of bone marrow-derived mesenchymal stem cells via the regulation of hypoxia inducible factor 1α

MicroRNA-519d-3p Inhibits Proliferation and Promotes Apoptosis by Targeting HIF-2α in Cervical Cancer Under Hypoxic Conditions

JAK1 inactivation promotes proliferation and migration of endometrial cancer cells via upregulating the hypoxia-inducible factor signaling pathway

Similar Documents

Vitamin D/VDR signaling inhibits LPS-induced IFNγ and IL-1β in Oral epithelia by regulating hypoxia-inducible factor-1α signaling pathway

Hypoxia-inducible factor 2α (HIF-2α) promotes colon cancer growth by potentiating Yes-associated protein 1 (YAP1) activity

Hypoxia-inducible factor (HIF) network: insights from mathematical models

Autocrine motility factor promotes endometrial cancer progression by targeting GPER-1

Correction: Adiponectin affects the migration ability of bone marrow-derived mesenchymal stem cells via the regulation of hypoxia inducible factor 1α

Interaction with ErbB4 Promotes Hypoxia-inducible Factor-1α Signaling

Hypoxia-inducible factor 2α (HIF-2α) promotes colon cancer growth by potentiating Yes-associated protein 1 (YAP1) activity

Adiponectin affects the migration ability of bone marrow-derived mesenchymal stem cells via the regulation of hypoxia inducible factor 1α

MicroRNA-519d-3p Inhibits Proliferation and Promotes Apoptosis by Targeting HIF-2α in Cervical Cancer Under Hypoxic Conditions

JAK1 inactivation promotes proliferation and migration of endometrial cancer cells via upregulating the hypoxia-inducible factor signaling pathway