Bioinformatic and Experimental Analyses Reveal That KIF4A Is a Biomarker of Therapeutic Sensitivity and Predicts Prognosis in Cervical Cancer Patients

Abstract

Objective

This study aims to investigate the expression, prognostic value, and function of kinesin superfamily 4A (KIF4A) in cervical cancer.

Methods

Cervical cancer cell lines (Hela and SiHa) and TCGA data were used for experimental and bioinformatic analyses. Overall survival (OS) and progression free survival (PFS) were compared between patients with high or low KIF4A expression. Copy number variation (CNV) and somatic mutations of patients were visualized and GISTIC 2.0 was used to identify significantly altered sites. The function of KIF4A was also explored based on transcriptome analysis and validated by experimental methods. Chemotherapeutic and immunotherapeutic benefits were inferred using multiple reference databases and algorithms.

Results

Patients with high KIF4A expression had better OS and PFS. KIF4A could inhibit proliferation and migration and induce G₁ arrest of cervical cancer cells. Higher CNV load was observed in patients with low KIF4A expression, while the group with low KIF4A expression displayed more significantly altered sites. A total of 13 genes were found to mutate more in the low KIF4A expression group, including NOTCH1 and PUM1. The analysis revealed that low KIF4A expression may indicate an immune escape phenotype, and patients in this group may benefit more from immunotherapy. With respect to chemotherapy, cisplatin and gemcitabine may respond better in patients with high KIF4A expression, while 5-fluorouracil etc. may be responded better in patients with low KIF4A expression

Conclusion

KIF4A is a tumor suppressor gene in cervical cancer, and it can be used as a prognostic and therapeutic biomarker in cervical cancer.

Keywords

kinesin superfamily 4A / cervical cancer / prognosis / chemotherapy / immunotherapy

References

[1] SiegelRL, MillerKD, FuchsHE, et al.. Cancer statistics, 2021. CA Cancer J Clin, 2021, 71(1): 7-33

[2] HaMJ, YoonJ, MoonE, et al.. Assignment of the kinesin family member 4 genes (KIF4A and KIF4B) to human chromosome bands Xq13.1 and 5q33.1 by in situ hybridization. Cytogenet Cell Genet, 2000, 88(1–2): 41-42

[3] ShengL, HaoSL, YangWX, et al.. The multiple functions of kinesin-4 family motor protein KIF4 and its clinical potential. Gene, 2018, 678: 90-99

[4] WanQ, ShenY, ZhaoH, et al.. Impaired DNA double-strand breaks repair by kinesin family member 4A inhibition renders human H1299 non-small-cell lung cancer cells sensitive to cisplatin. J Cell Physiol, 2019, 234(7): 10360-10371

[5] PanLN, ZhangY, ZhuCJ, et al.. Kinesin KIF4A is associated with chemotherapeutic drug resistance by regulating intracellular trafficking of lung resistance-related protein. J Zhejrang Univ Sci B, 2017, 18(12): 1046-1054

[6] TaniwakiM, TakanoA, IshikawaN, et al.. Activation of KIF4A as a prognostic biomarker and therapeutic target for lung cancer. Clin Cancer Res, 2007, 13(22): 6624-6631 Pt 1

[7] GaoJ, SaiN, WangC, et al.. Overexpression of chromokinesin KIF4 inhibits proliferation of human gastric carcinoma cells both in vitro and in vivo. Tumour Biol, 2011, 32(1): 53-61

[8] TomczakK, CzerwinskaP, WiznerowiczM. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol (Pozn), 2015, 19(1A): A68-A77

[9] PengL, LiJ, WuJ, et al.. A pan-cancer analysis of SMARCA4 alterations in human cancers. Front Immunol, 2021, 12: 762598

[10] WuJ, LiL, ZhangH, et al.. A risk model developed based on tumor microenvironment predicts overall survival and associates with tumor immunity of patients with lung adenocarcinoma. Oncogene, 2021, 40(26): 4413-4424

[11] HoadleyKA, YauC, HinoueT, et al.. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell, 2018, 173(2): 291-304e6

[12] MaeserD, GruenerRF, HuangRS. oncoPredict: an R package for predicting in vivo or cancer patient drug response and biomarkers from cell line screening data. Brief Bioinform, 2021, 22(6): bbab260

[13] YangC, HuangX, LiY, et al.. Prognosis and personalized treatment prediction in TP53-mutant hepatocellular carcinoma: an in silico strategy towards precision oncology. Brief Bioinform, 2021, 22(3): bbaa164

[14] JiangP, GuS, PanD, et al.. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med, 2018, 24(10): 1550-1558

[15] CharoentongP, FinotelloF, AngelovaM, et al.. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep, 2017, 18(1): 248-262

[16] HoshidaY, BrunetJP, TamayoP, et al.. Subclass mapping: identifying common subtypes in independent disease data sets. PLoS One, 2007, 2(11): e1195

[17] LuX, JiangL, ZhangL, et al.. Immune signature-based subtypes of cervical squamous cell carcinoma tightly associated with human papillomavirus type 16 expression, molecular features, and clinical outcome. Neoplasia, 2019, 21(6): 591-601

[18] JungwirthG, YuT, MoustafaM, et al.. Identification of KIF11 as a novel target in meningioma. Cancers (Basel), 2019, 11(4): 545

[19] FuC, YanF, WuF, et al.. Mitotic phosphorylation of PRC1 at Thr470 is required for PRC1 oligomerization and proper central spindle organization. Cell Res, 2007, 17(5): 449-457

[20] NguyenPA, GroenAC, LooseM, et al.. Spatial organization of cytokinesis signaling reconstituted in a cell-free system. Science, 2014, 346(6206): 244-247

[21] ChenJ, RajasekaranM, XiaH, et al.. The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/beta-catenin signalling pathway. Gut, 2016, 65(9): 1522-1534

[22] ZhangL, HuangQ, LouJ, et al.. A novel PHD-finger protein 14/KIF4A complex overexpressed in lung cancer is involved in cell mitosis regulation and tumorigenesis. Oncotarget, 2017, 8(12): 19684-19698

[23] LucanusAJ, YipGW. Kinesin superfamily: roles in breast cancer, patient prognosis and therapeutics. Oncogene, 2018, 37(7): 833-838

[24] ZhuD, XuX, ZhangM, et al.. Enhanced expression of KIF4A in osteosarcoma predicts a poor prognosis and facilitates tumor growth by activation of the MAPK pathway. Exp Ther Med, 2021, 22(5): 1339

[25] HuG, YanZ, ZhangC, et al.. FOXM1 promotes hepatocellular carcinoma progression by regulating KIF4A expression. J Exp Clin Cancer Res, 2019, 38(1): 188

[26] SunX, ChenP, ChenX, et al.. KIF4A enhanced cell proliferation and migration via Hippo signaling and predicted a poor prognosis in esophageal squamous cell carcinoma. Thorac Cancer, 2021, 12(4): 512-524

[27] HouPF, JiangT, ChenF, et al.. KIF4A facilitates cell proliferation via induction of p21-mediated cell cycle progression and promotes metastasis in colorectal cancer. Cell Death Dis, 2018, 9(5): 477

[28] LiuG, LuY, LiL, et al.. The kinesin motor protein KIF4A as a potential therapeutic target in renal cell carcinoma. Invest New Drugs, 2020, 38(6): 1730-1742

[29] Ronnov-JessenL, PetersenOW, KotelianskyVE, et al.. The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest, 1995, 95(2): 859-873

[30] LeBleuVS, TaduriG, O’ConnellJ, et al.. Origin and function of myofibroblasts in kidney fibrosis. Nat Med, 2013, 19(8): 1047-1053

[31] LiuYT, SunZJ. Turning cold tumors into hot tumors by improving T-cell infiltration. Theranostics, 2021, 11(11): 5365-5386

[32] WangH, LuC, LiQ, et al.. The role of KIF4A in doxorubicin-induced apoptosis in breast cancer cells. Mol Cells, 2014, 37(11): 812-818

[33] RashmiR, DeSelmC, HelmsC, et al.. AKT inhibitors promote cell death in cervical cancer through disruption of mTOR signaling and glucose uptake. PLoS One, 2014, 9(4): e92948

[34] TaoL, LiuS, XiongJ, et al.. IL-1beta promotes cervical cancer through activating NF-kappaB/CCL-2. Int J Clin Exp Pathol, 2021, 14(4): 426-433