HIF1α and HIF2α independently activate SRC to promote melanoma metastases

Hanna, Sara C.; Krishnan, Bhavani; Bailey, Sean T.; Moschos, Stergios J.; Kuan, Pei Fen; Shimamura, Takeshi; Osborne, Lukas D.; Siegel, Marni B.; Duncan, Lyn M.; O’Brien, E. Timothy; Superfine, R.; Miller, C. Ryan; Simon, M. Celeste; Wong, Kwok-Kin; Kim, William Y.

doi:10.1172/jci66715

Cited by 134 publications

(128 citation statements)

References 41 publications

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“…In addition, HIF-1α is decreased by inhibiting ERK pathway in cervical carcinoma CaSki cells [47], but apoptosis is enhanced by HIF-1α knockdown in pancreatic cancerous BxPC-3 cells [48]. HIF-1α also promotes cell migration by regulating MMP-2 [49] and FAK [50], which is in line with our current data. These results showed SDHB might affect cancer cell proliferation, invasion, migration, and apoptosis via AMPK-HIF-1α in ovarian carcinoma.…”

Section: Discussionsupporting

confidence: 89%

Succinate dehydrogenase subunit B inhibits the AMPK-HIF-1¿ pathway in human ovarian cancer in vitro

Chen

Liu

Zhang

et al. 2014

Journal of Ovarian Research

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Background: Ovarian carcinoma is one of the most common gynecological cancers with high mortality rates. Numerous evidences demonstrate that cancer cells undergo metabolic abnormality during tumorigenesis in tumor microenvironment and further facilitate tumor progression. Succinate dehydrogenase (SDH or Complex II) is one of the important enzymes in the tricarboxylic acid (TCA) cycle. Succinate dehydrogenase subunit B (SDHB) gene, which encodes one of the four subunits of SDH, has been recognized as a tumor suppressor. However the role of SDHB in ovarian cancer is still unclear. Methods: Using the SDHB specific siRNA and overexpression plasmid, the expression of SDHB was silenced and conversely induced in ovarian cancer cell lines SKOV3 and A2780, respectively. The possible role of SDHB in ovarian cancer was investigated in vitro, using proliferation, migration and invasion assays. To explore the mechanism, proliferation and migration related proteins such as Bcl-2, cleaved caspase 3, p-ERK, MMP-2, and p-FAK were examined by western blot. P-P38, p-AMPKα, and HIF-1α were also examined by western blot. CoCl2 was used to induce HIF-1α expression in SKOV3 and A2780 cells.

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Section: Discussionsupporting

confidence: 89%

Succinate dehydrogenase subunit B inhibits the AMPK-HIF-1¿ pathway in human ovarian cancer in vitro

Chen

Liu

Zhang

et al. 2014

Journal of Ovarian Research

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“…Although SRC plays a central role in mediating multiple protumorigenic signaling cascades, it is rarely mutated in cancers (32). In melanoma, HIF-1 and HIF-2 activate SRC through PDGFRα and FAK to mediate cellular invasion (40). Our data suggest that a mechanism for SRC activation in ccRCC occurs through HIF-mediated up-regulation of GAS6/AXL signaling where AXL directly binds to and activates SRC activity.…”

Section: Discussionmentioning

confidence: 78%

Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET

Rankin

Fuh

Castellini

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

242

210

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Dysregulation of the von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) signaling pathway promotes clear cell renal cell carcinoma (ccRCC) progression and metastasis. The protein kinase GAS6/AXL signaling pathway has recently been implicated as an essential mediator of metastasis and receptor tyrosine kinase crosstalk in cancer. Here we establish a molecular link between HIF stabilization and induction of AXL receptor expression in metastatic ccRCC. We found that HIF-1 and HIF-2 directly activate the expression of AXL by binding to the hypoxia-response element in the AXL proximal promoter. Importantly, genetic and therapeutic inactivation of AXL signaling in metastatic ccRCC cells reversed the invasive and metastatic phenotype in vivo. Furthermore, we define a pathway by which GAS6/AXL signaling uses lateral activation of the met proto-oncogene (MET) through SRC proto-oncogene nonreceptor tyrosine kinase to maximize cellular invasion. Clinically, AXL expression in primary tumors of ccRCC patients correlates with aggressive tumor behavior and patient lethality. These findings provide an alternative model for SRC and MET activation by growth arrest-specific 6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma.targeted therapy | kidney cancer | VHL | hepatocellular carcinoma K idney cancer is a leading cause of cancer-related deaths in the United States. Metastasis to distant organs including the lung, bone, liver, and brain is the primary cause of death in kidney cancer patients, as only 12% of patients with metastatic kidney cancer will survive past 5 y, in comparison with 92% of patients with a localized disease (1). Because kidney cancer is chemo-and radiation-resistant, targeted therapies are needed for the prevention and management of metastatic kidney cancer.The von Hippel-Lindau (VHL)-hypoxia-inducible transcription factor (HIF) pathway is a critical regulator of clear cell renal cell carcinoma (ccRCC) tumor initiation and metastasis. VHL is a classic tumor suppressor controlling tumor initiation in ∼90% of ccRCC tumors (2, 3). VHL is the substrate recognition component of an E3 ubiquitin ligase complex containing the elongins B and C (4, 5), Cullin-2 (6), and Rbx1 (7) that targets the hydroxylated, oxygen-sensitive α-subunits of HIFs (HIF-1, -2, and -3) for ubiquitination and degradation by the 26S proteasome (8, 9). Thus, the primary function ascribed to VHL is the regulation of HIF protein stability. In VHL-deficient tumors, HIF transcriptional activity is constitutively active and contributes to both ccRCC tumor initiation and metastasis (8-11). Although many downstream HIF targets controlling ccRCC tumor initiation have been defined, key targets involved in ccRCC metastasis remain to be identified.AXL, a member of the TAM family of receptor tyrosine kinases (RTKs), has recently been described as an essential mediator of cancer metastasis. Additionally, AXL has been reported to mediate RTK crosstalk and resistance to targeted kina...

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“…As HIF-1a is known to be a core gene for affecting the biological behavior of malignant melanoma, 12 we hypothesized that miR-33a abnormally expressed in melanoma could exert biological functions in inhibition of tumor cell proliferation, metastasis and invasion at least through partially targeting HIF-1a.…”

Section: Mir-33a Directly Targets Hif-1amentioning

confidence: 99%

miR-33a functions as a tumor suppressor in melanoma by targeting HIF-1α

Zhou¹,

Xie

et al. 2015

Cancer Biology & Therapy

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Abbreviations: miR-33a/b, microRNA 33a/b; HIF-1a, hypoxia inducible factor 1, a subunit Background: Our previous findings showed that miR-33 expressed abnormally in clinical specimens of melanoma, but the exact molecular mechanism has not been elucidated. Object: To determine miR-33's roles in melanoma and confirm whether HIF-1a is a direct target gene of miR-33a. Methods: First miR-33a/b expression levels were detected in HM, WM35, WM451, A375 and SK-MEL-1. Then lentiviral vectors were constructed to intervene miR-33a expression in melanoma cells. Cell proliferation, invasion and metastasis were detected. A375 cells mice model was performed to test the tumorigenesis of melanoma in vivo. Finally the dual reporter gene assay was carried out to confirm whether HIF-1a is a direct target gene of miR-33a. Results: MiR-33a/b exhibited a lower expression in WM35, WM451, A375 and SK-MEL-1 of the metastatic skin melanoma cell lines than that in HM. Then inhibition of miR-33a expression in WM35 and WM451 cell lines could promote cell proliferation, invasion and metastasis. Conversely, increased expression of miR-33a in A375 cells could inhibit cellproliferation, invasion and metastasis. In vivo tests also confirmed that overexpression of miR-33a in A375 cells significantly inhibited melanoma tumorigenesis. Finally, we confirmed that HIF-1a is a direct target gene of miR-33a. Conclusion: The newly identified miR-33a/HIF-1a axis might provide a new strategy for the treatment of melanoma.

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HIF1α and HIF2α independently activate SRC to promote melanoma metastases

Cited by 134 publications

References 41 publications

Succinate dehydrogenase subunit B inhibits the AMPK-HIF-1¿ pathway in human ovarian cancer in vitro

Succinate dehydrogenase subunit B inhibits the AMPK-HIF-1¿ pathway in human ovarian cancer in vitro

Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET

miR-33a functions as a tumor suppressor in melanoma by targeting HIF-1α

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