Focal adhesion molecule Kindlin-1 mediates activation of TGF-β signaling by interacting with TGF-βRI, SARA and Smad3 in colorectal cancer cells

Kong, Jinfeng; Du, Juan; Wang, Yunling; Yang, Miao; Gao, Jianchao; Wei, Xiaofan; Fang, Wei‐Gang; Zhan, Jun; Zhang, Hongquan

doi:10.18632/oncotarget.12779

Cited by 21 publications

(14 citation statements)

References 31 publications

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“…Tumors can be implanted into the interscapular fat pad, the mammary fat pad or in the flank. Xenografts appear at the graft site 1–12 months after grafting, they are subsequently transplanted from mouse to mouse; adapted from [ 44 ]. Then, Kindlins transcript levels were assessed in bulk tumors by using species-specific primers (mean ± SE values are represented) …”

Section: Resultsmentioning

confidence: 99%

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Distinct expression profiles and functions of Kindlins in breast cancer

Azorin

Bonin

Moukachar

et al. 2018

J Exp Clin Cancer Res

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BackgroundKindlin-1, − 2, and − 3 are the three members of the Kindlin family. They are best known as regulators of integrin functions, contributing to fundamental biological processes such as cell survival, adhesion and migration. Their deregulation leads to diverse pathologies including a broad range of cancers in which both, tumor-promoting and tumor-inhibiting functions have been described.MethodsTo better characterize Kindlins implication in breast cancer, in vitro experiments were performed in a series of cancer cell lines. We first assessed their expression profiles and subcellular distributions. Then, their involvement in breast cancer cell morphology, migration and invasion was verified by examining phenotypic changes induced by the depletion of either isoforms using RNA interference. An expression study was performed in a series of breast cancer patient derived xenografts (n = 58) to define the epithelial and stromal contribution of each Kindlin. Finally, we analyzed the expression levels of the three Kindlins in a large series of human breast tumors, at the RNA (n = 438) and protein (n = 129) levels and we evaluated their correlation with the clinical outcome.ResultsWe determined that Kindlin-1 and Kindlin-2, but not Kindlin-3, were expressed in breast tumor cells. We uncovered the compensatory roles of Kindlin-1 and -2 in focal adhesion dynamics and cell motility. Remarkably, Kindlin-2 had a predominant effect on cell spreading and Kindlin-1 on cell invasion. In line with these experimental observations, Kindlin-1 overexpression was associated with a worse patients’ outcome. Notably, Kindlin-3, expressed by tumor infiltrating leukocytes, also correlated with a poor prognosis of breast cancer patients.ConclusionThis study demonstrates that each one of the Kindlin family members has a different expression profile emphasizing their redundant and complementary roles in breast tumor cells. We highlight the specific link between Kindlin-1 and breast cancer progression. In addition, Kindlin-3 overexpression in the tumor microenvironment is associated with more aggressive breast tumors.These results suggest that Kindlins play distinctive roles in breast cancer. Kindlins may be useful in identifying breast cancer patients with a worst prognosis and may offer new avenues for therapeutic intervention against cancer progression.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0955-4) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

“…In agreement with our observations in breast cancer, other groups have also demonstrated the role of Kindlin-1 in cell invasion in distinct cancer types including pancreatic and colorectal carcinomas. In these cancers, the up-regulation of Kindlin-1 was also correlated with cancer progression and poor patient outcomes [ 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

Distinct expression profiles and functions of Kindlins in breast cancer

Azorin

Bonin

Moukachar

et al. 2018

J Exp Clin Cancer Res

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“…are significantly associated with the risk of developing human colorectal cancer and may have great importance in tumor metastasis (19,78,79). It is generally believed that TGF-β1 can restrain the proliferation of tumor cells since it suppresses the proliferation of epithelial cells in vitro; additionally, TGF-β1 promotes EcM remodeling, which may regulate the mutual effect between tumor cells and the matrix/epithelial cell differentiation (80).…”

Section: Tgf-β Tgf-βr1 and Malignant Tumorsmentioning

confidence: 99%

“…Colorectal cancer is the third most common cause of cancer-associated death in both men and women in the United States according to the American Cancer Society, with ~147,950 individuals diagnosed with CRC and 53,200 who died from the disease in 2020 ( 77 ). In previous years, some studies have revealed that TGF-β1 and TGF-βR1 are significantly associated with the risk of developing human colorectal cancer and may have great importance in tumor metastasis ( 19 , 78 , 79 ). It is generally believed that TGF-β1 can restrain the proliferation of tumor cells since it suppresses the proliferation of epithelial cells in vitro ; additionally, TGF-β1 promotes ECM remodeling, which may regulate the mutual effect between tumor cells and the matrix/epithelial cell differentiation ( 80 ).…”

Section: Tgf-β Tgf-βr1 and Malignant Tumorsmentioning

confidence: 99%

Role and clinical significance of TGF‑β1 and TGF‑βR1 in malignant tumors (Review)

et al. 2021

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The appearance and growth of malignant tumors is a complicated process that is regulated by a number of genes. In recent years, studies have revealed that the transforming growth factor-β (TGF-β) signaling pathway serves an important role in cell cycle regulation, growth and development, differentiation, extracellular matrix synthesis and immune response. Notably, two members of the TGF-β signaling pathway, TGF-β1 and TGF-β receptor 1 (TGF-βR1), are highly expressed in a variety of tumors, such as breast cancer, colon cancer, gastric cancer and hepatocellular carcinoma. Moreover, an increasing number of studies have demonstrated that TGF-β1 and TGF-βR1 promote proliferation, migration and epithelial-mesenchymal transition of tumor cells by activating other signaling pathways, signaling molecules or microRNAs (miRs), such as the NF-κB signaling pathway and miR-133b. In addition, some inhibitors targeting TGF-β1 and TGF-βR1 have exhibited positive effects in in vitro experiments. The present review discusses the association between TGF-β1 or TGF-βR1 and tumors, and the development of some inhibitors, hoping to provide more approaches to help identify novel tumor markers to restrain and cure tumors.

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“…Recently, Kindling-1 has been identified as directly interacting with the key TGFβ/SMAD3 signaling components in numerous CRC cell lines (SW1116, SW480, SW620, Caco2, HCT116, RKO, LST and HT29). Kindlin-1 expression has been found to correlate with the progression of CRC and poor prognosis ( 96 ).…”

Section: The Characteristics Of Crc-cscs Being Considered For Csc-tarmentioning

confidence: 99%

Therapeutic strategies against cancer stem cells in human colorectal cancer (Review)

et al. 2017

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Colorectal cancer (CRC) is the third most frequent malignancy and represents the fourth most common cause of cancer-associated mortalities in the world. Despite many advances in the treatment of CRC, the 5-year survival rate of patients with CRC remains unsatisfactory due to tumor recurrence and metastases. Recently, cancer stem cells (CSCs), have been suggested to be responsible for the initiation and relapse of the disease, and have been identified in CRC. Due to their basic biological features, which include self-renewal and pluripotency, CSCs may be novel therapeutic targets for CRC and other cancer types. Conventional therapeutics only act on proliferating and mature cancer cells, while quiescent CSCs survive and often become resistant to chemotherapy. In this review, markers of CRC-CSCs are evaluated and the recently introduced experimental therapies that specifically target these cells by inducing CSC proliferation, differentiation and sensitization to apoptotic signals via molecules including Dickkopf-1, bone morphogenetic protein 4, Kindlin-1, tankyrases, and p21-activated kinase 1, are discussed. In addition, novel strategies aimed at inhibiting some crucial processes engaged in cancer progression regulated by the Wnt, transforming growth factor β and Notch signaling pathways (pyrvinium pamoate, silibinin, PRI-724, P17, and P144 peptides) are also evaluated. Although the metabolic alterations in cancer were first described decades ago, it is only recently that the concept of targeting key regulatory molecules of cell metabolism, such as sirtuin 1 (miR-34a) and AMPK (metformin), has emerged. In conclusion, the discovery of CSCs has resulted in the definition of novel therapeutic targets and the development of novel experimental therapies for CRC. However, further investigations are required in order to apply these novel drugs in human CRC.

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Focal adhesion molecule Kindlin-1 mediates activation of TGF-β signaling by interacting with TGF-βRI, SARA and Smad3 in colorectal cancer cells

Cited by 21 publications

References 31 publications

Distinct expression profiles and functions of Kindlins in breast cancer

Distinct expression profiles and functions of Kindlins in breast cancer

Role and clinical significance of TGF‑β1 and TGF‑βR1 in malignant tumors (Review)

Therapeutic strategies against cancer stem cells in human colorectal cancer (Review)

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