Oncogenic K-Ras upregulates ITGA6 expression via FOSL1 to induce anoikis resistance and synergizes with αV-Class integrins to promote EMT

Zhang, Kai; Myllymäki, Satu-Marja; Gao, Ping; Devarajan, Raman; Kytölä, Ville; Nykter, Matti; Wei, Gong-Hong; Manninen, Aki

doi:10.1038/onc.2017.177

Cited by 58 publications

(48 citation statements)

References 73 publications

(88 reference statements)

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“…To generate double ␣6/␤4-KO and ␤1/␤4-KO cells, clonal ␤4KO cells were transduced with ␣6-targeting lentiCRISPR vector as described above, expanded and negatively selected by fluorescence activated cell sorting (FACS) based on live staining with anti-␣6 (GoH3) or anti-␤1 (AIIB2) antibodies. Antibody staining for FACS was performed as previously described (28). Alexa Fluor 488-negative cell population was collected with the BD FACSAria™ flow cytometer (BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

Assembly of the β4-Integrin Interactome Based on Proximal Biotinylation in the Presence and Absence of Heterodimerization*

Myllymäki

Kämäräinen

Liu

et al. 2019

Molecular & Cellular Proteomics

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This study characterized the ␤4integrin interacting proteome using BioID proximity-dependent biotinylation in epithelial MDCK cells. The analysis identified several novel type II hemidesmosome (HD)-associated proteins and revealed potential connecting protein modules that could orchestrate the observed coordinated coassembly of HDs and focal adhesions (FAs). Curiously, unlike the formation of HDs, the assembly of ␤4-interactome did not depend on ␣6␤4heterodimerization.

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Section: Methodsmentioning

confidence: 99%

Assembly of the β4-Integrin Interactome Based on Proximal Biotinylation in the Presence and Absence of Heterodimerization*

Myllymäki

Kämäräinen

Liu

et al. 2019

Molecular & Cellular Proteomics

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“…Integrin has been shown to affect tumorigenesis via the Ras/Erk pathway [19]. However, whether ITGA1 affects tumorigenesis of CRC via the Ras/Erk pathway requires further to investigate.…”

Section: Itga1 Activates the Ras/erk Signaling Pathwaymentioning

confidence: 99%

Integrin α1 promotes tumorigenicity and progressive capacity of colorectal cancer

Li¹,

Wang²,

Rong³

et al. 2020

Int. J. Biol. Sci.

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Colorectal cancer (CRC) is the second leading cause of death globally. Integrin α1 (ITGA1) belongs to integrin family and involves in regulating cell adhesion, invasion, proliferation and tumorigenicity, its expression is up-regulated in various cancers, including CRC. However, the molecular understanding and clinical relevance of ITGA1 in the development and progression of CRC remain unclear. In the present study, we detected ITGA1 in 50 CRC tissues and adjacent non-cancerous tissues, sera from 100 CRC patients and 50 healthy subjects, and four CRC cell lines using immunohistochemistry staining, enzyme-linked immunosorbent assay and Western blotting. We found that the ITGA1 protein was significantly higher in human CRC tissues and cell lines than both paired non-tumor tissues and normal cells, respectively. In addition, the serum concentration of ITGA1 was also higher in CRC patients compared to the healthy subjects (p<0.01) and was significantly associated with metastatic TNM stages (p<0.0001) and circulating carbohydrate antigen 199 (CA199) (p<0.022). Furthermore, down-regulation of ITGA1 with transfecting LV-shITGA1 inhibited the progressive capacity of cell migration and invasion in CRC SW480 cell line and the tumorgenicity in nude mice. In functional studies, ITGA1 knockdown also inhibited Ras/ERK signaling pathway by decreasing the expression of Ras, p-Erk1/2 and c-Myc in SW480. Contrastly, when evelated expression of ITGA1 in NCM460 coincided with the increased expression of Ras, p-Erk1/2 and c-Myc. Taken together, our findings suggest that ITGA1 is an oncogene with a capability to promote CRC cell migration, invasion and tumorigenicity by activating the Ras/Erk signaling, implying that it may be a novel target for the diagnosis and treatment of CRC, and warrants further investigation.

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“…K‐RAS protooncogene is one of the genes with high mutation frequency of >90% in PC, which is closely related to the development of PC and confers a unfavourable prognosis in PC patients . The somatic mutation in K‐RAS was confirmed to promote the malignant transformation of tumour cells and resistance to anticancer agents . Studies have reported that the PC cells lines carrying mutated K‐RAS showed high resistance to gemcitabine .…”

Section: Introductionmentioning

confidence: 99%

“…[7] The somatic mutation in K-RAS was confirmed to promote the malignant transformation of tumour cells and resistance to anticancer agents. [8] Studies have reported that the PC cells lines carrying mutated K-RAS showed high resistance to gemcitabine. [9] Recent evidence also suggested that mutations of K-RAS predicted an insensitivity of PC cells to erlotinib.…”

Section: Introductionmentioning

confidence: 99%

Targeting EphA2 with miR-124 mediates Erlotinib resistance in K-RAS mutated pancreatic cancer

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Chemotheraputic drug resistance is a critical factor associated with the poor survival in advanced/metastatic pancreatic cancer (PC) patients. Methods Human pancreatic cell lines Capan‐1 and BXPC‐3 were cultured with different concentrations of erlotinib (0, 10, 50, and 100 μm) for 48 h. The relative cell viability and apoptosis was detected using MTT assays and flow cytometry apoptosis analysis, respectively. Transfection of pcDNA‐EphA2, si‐EphA2 and miR‐124 mimic/inhibitor was used to modulate the intracellular level of EphA2 and miR‐124. The interaction between miR‐124 and the 3′UTR of EphA2 was explored using dual luciferase reporter assay. Key findings Compared with BXPC‐3 cells, Capan‐1 cells showed resistance to differential concentration treatment of erlotinib. The expression of EphA‐2 was significantly increased and the expression of miR‐124 was significantly decreased in Capan‐1 cells. Overexpressing EphA2 induced resistance of BXPC‐3 cells to erlotinib treatment. And EphA2 was identified as a novel target gene for miR‐124. MiR‐124 overexpression was able to sensitize the response of Capan‐1 cells to erlotinib through inhibiting EphA2. Furthermore, both miR‐124 overexpression and EphA2 inhibition sensitized Capan‐1 cells to erlotinib in xenograft model. Conclusions Our study demonstrated that EphA2 rescued by miR‐124 downregulation conferred the erlotinib resistance of PC cell Capan‐1 with K‐RAS mutation.

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Oncogenic K-Ras upregulates ITGA6 expression via FOSL1 to induce anoikis resistance and synergizes with αV-Class integrins to promote EMT

Cited by 58 publications

References 73 publications

Assembly of the β4-Integrin Interactome Based on Proximal Biotinylation in the Presence and Absence of Heterodimerization*

Assembly of the β4-Integrin Interactome Based on Proximal Biotinylation in the Presence and Absence of Heterodimerization*

Integrin α1 promotes tumorigenicity and progressive capacity of colorectal cancer

Targeting EphA2 with miR-124 mediates Erlotinib resistance in K-RAS mutated pancreatic cancer

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