KRT17 promotes endometrial cancer cell migration as well as angiogenesis by regulating HIF-1α/VEGF pathway

Endometrial cancer (EC) is a common type malignant tumors in women. To combat this type of cancer, more effective treatments are still needed. EC cell growth and metastasis depend on angiogenesis. Keratin (KRT) is a family of proteins which are essential for hair formation. KRT17 affected a variety of cancers. Here, we reported that KRT17 expression was high in human EC. The depletion of KRT17 suppressed EC cell growth. We further showed the ablation of KRT17 led to the suppression of cell motility. Also, its depletion resulted in the inhibition of angiogenesis. We further demonstrated that KRT17 contributed to the progression of EC via regulating the HIF-1α/VEGF axis through a tumor growth assay in mice. In conclusion, KRT17 could serve as an EC target.

Endometrial cancer (EC); Keratin 17 (KRT17); Angiogenesis; Motility; HIF-1α/VEGF axis

[1] Jooya ND, Ciccone MA, Brunette LL, Pham HQ, Yessaian AA, Muder-spach LI, et al. Population-level uptake of neoadjuvant chemotherapy for stage IVB endometrial cancer. Gynecologic Oncology. 2022; 165: 428–436.

[2] Español P, Luna R, Soler C, Caruana P, Altés-Arranz A, Rodríguez F, et al. Neural plasticity of the uterus: new targets for endometrial cancer?Women’s Health. 2022; 18: 174550572210955.

[3] Burnell M, Gentry-Maharaj A, Glazer C, Karpinskyj C, Ryan A, Apostolidou S, et al. Serial endometrial thickness and risk of non-endometrial hormone-dependent cancers in postmenopausal women in UK collaborative trial of ovarian cancer screening. Ultrasound in Obstetrics & Gynecology. 2020; 56: 267–275.

[4] Camilloni A, Nati G, Maggiolini P, Romanelli A, Latina R. Chronic non-cancer pain in primary care: an Italian cross-sectional study. Signa Vitae. 2021; 7: 54–62.

[5] Kang S, Thompson Z, McClung EC, Abdallah R, Lee JK, Gonzalez-Bosquet J, et al. Gene expression signature-based prediction of lymph node metastasis in patients with endometrioid endometrial cancer. International Journal of Gynecological Cancer. 2018; 28: 260–266.

[6] Tung HJ, Wu RC, Lin CY, Lai CH. Rare subtype of endometrial cancer: undifferentiated/dedifferentiated endometrial carcinoma, from genetic aspects to clinical practice. International Journal of Molecular Sciences. 2022; 23: 3794.

[7] Fantin A, Ruhrberg C. The embryonic mouse hindbrain and postnatal retina as in vivo models to study angiogenesis. Methods in Molecular Biology. 2022; 16: 275–287.

[8] Tang Z, Xie H, Jiang S, Cao S, Pu Y, Zhou B, et al. Safflower yellow promotes angiogenesis through p-VHL/HIF-1α/VEGF signaling pathway in the process of osteogenic differentiation. Biomedicine & Pharmacotherapy. 2018; 107: 1736–1743.

[9] Chen HY, Zhou ZY, Luo YL, Luo Q, Fan JT. Knockdown of YKL-40 inhibits angiogenesis through regulation of VEGF/VEGFR2 and ERK1/2 signaling in endometrial cancer. Cell Biology International. 2021; 45: 2557–2566.

[10] Pang B, Zhu Z, Xiao C, Luo Y, Fang H, Bai Y, et al. Keratin 17 is required for lipid metabolism in keratinocytes and benefits epidermal permeability barrier homeostasis. Frontiers in Cell and Developmental Biology. 2021; 9: 779257.

[11] Bhattacharji P, Moore W, Yaddanapudi K. Keratin 17 is an imaging biomarker in lung cancers. Journal of Thoracic Disease. 2020; 12: 5062–5066.

[12] Li C, Teng Y, Wu J, Yan F, Deng R, Zhu Y, et al. A pan-cancer analysis of the oncogenic role of Keratin 17 (KRT17) in human tumors. Translational Cancer Research. 2021; 10: 4489–4501.

[13] Liu J, Liu L, Cao L, Wen Q. Keratin 17 promotes lung adenocarcinoma progression by enhancing cell proliferation and invasion. Medical Science Monitor. 2018; 24: 4782–4790.

[14] Liu Z, Yu S, Ye S, Shen Z, Gao L, Han Z, et al. Keratin 17 activates AKT signalling and induces epithelial-mesenchymal transition in oesophageal squamous cell carcinoma. Journal of Proteomics. 2020; 211: 103557.

[15] Li C, Su H, Ruan C, Li X. Keratin 17 knockdown suppressed malignancy and cisplatin tolerance of bladder cancer cells, as well as the activation of AKT and ERK pathway. Folia Histochem Cytobiol. 2021; 59: 40–48.

[16] Sankar S, Tanner JM, Bell R, Chaturvedi A, Randall RL, Beckerle MC, et al. A novel role for Keratin 17 in coordinating oncogenic transformation and cellular adhesion in Ewing sarcoma. Molecular and Cellular Biology. 2013; 33: 4448–4460.

[17] Králíčková M, Vetvicka V, Laganà AS. Endometrial cancer—is our knowledge changing? Translational Cancer Research. 2020; 9: 7734–7745.

[18] Pitakkarnkul S, Chanpanitkitchot S, Tangjitgamol S. Management of inoperable endometrial cancer. Obstetrics & Gynecology Science. 2022; 65: 303–316.

[19] Li M, Rao X, Cui Y, Zhang L, Li X, Wang B, et al. The keratin 17/YAP/IL6 axis contributes to E-cadherin loss and aggressiveness of diffuse gastric cancer. Oncogene. 2022; 41: 770–781.

[20] Nair RR, Hsu J, Jacob JT, Pineda CM, Hobbs RP, Coulombe PA. A role for keratin 17 during DNA damage response and tumor initiation. Proceedings of the National Academy of Sciences. 2021; 118: e2020150118.

[21] Yan X, Yang C, Hu W, Chen T, Wang Q, Pan F, et al. Knockdown of KRT17 decreases osteosarcoma cell proliferation and the Warburg effect via the AKT/mTOR/HIF1α pathway. Oncology Reports. 2020; 44: 103–114.

[22] Ji R, Ji Y, Ma L, Ge S, Chen J, Wu S, et al. Keratin 17 upregulation promotes cell metastasis and angiogenesis in colon adenocarcinoma. Bioengineered. 2021; 12: 12598–12611.

[23] Jacob JT, Nair RR, Poll BG, Pineda CM, Hobbs RP, Matunis MJ, et al. Keratin 17 regulates nuclear morphology and chromatin organization. Journal of Cell Science. 2020; 133: jcs254094.

[24] Kretschmer M, Rudiger D, Zahler S. Mechanical aspects of angiogenesis. Cancers. 2021; 13: 4987.