RAB7A in Oral Squamous Cell Carcinoma: A Key Regulator of Autophagy-Lysosome Dynamics and Cellular Signaling

Yubin Pang; Linxuan Zhang; Yingjiu Wang; Yuwei Jia; Xintong Han; Wei Dong; Junyuan Zhang

doi:10.54097/4rnf8d12

Authors

Yubin Pang
Linxuan Zhang
Yingjiu Wang
Yuwei Jia
Xintong Han
Wei Dong
Junyuan Zhang

DOI:

https://doi.org/10.54097/4rnf8d12

Keywords:

RAB7A, Oral Squamous Cell Carcinoma, Signaling Pathway, Autophagy-lysosome

Abstract

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the head and neck region. Despite advances in treatment, its prognosis has remained poor over the years, largely due to its high invasiveness and resistance to therapy. A deeper understanding of the molecular mechanisms underlying OSCC initiation and progression is essential for the development of novel diagnostic and therapeutic strategies. This review summarizes the role of Ras-related protein Rab-7a (RAB7A) in various tumors and explores its potential functions in OSCC. We also discuss RAB7A-related research in oral diseases such as periodontitis and highlight its key role in regulating autophagic homeostasis and inflammatory responses via post-translational modifications. Furthermore, given the abnormal activation of signaling pathways such as Hippo/Yes-associated protein (Hippo/YAP), phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), and mitogen-activated protein kinase (MAPK) in OSCC, we infer the possibility that RAB7A may contribute to OSCC progression by mediating intracellular transport and integrating signals from these pathways. Overall, RAB7A serves as a pivotal hub molecule linking the autophagy-lysosome system to oncogenic signaling pathways. In-depth investigation of its role in OSCC is expected to provide precise target sites for targeted drug development, offer new insights into clinical combination therapy, and clarify the core function of RAB7A in the molecular regulatory network of OSCC, thereby establishing a direct association between autophagy regulatory pathways and OSCC progression.

Downloads

Download data is not yet available.

References

[1] Langemeyer L, Fröhlich F, Ungermann C. Rab GTPase function in endosome and lysosome biogenesis[J]. Trends in Cell Biology, 2018, 28(11): 957-970.

[2] Hewawasam NV, Lhaf F, Taylor HA, Viloria K, Austin A, King A, Jones P, Jones L, Turner MD, Hill NJ. Modulation of Rab7a-mediated growth factor receptor trafficking inhibits islet beta cell apoptosis and autophagy under conditions of metabolic stress. Sci Rep. 2020 Sep 25;10(1):15741.

[3] Bhattacharya A, Mukherjee R, Kuncha S K, et al. A lysosome membrane regeneration pathway depends on TBC1D15 and autophagic lysosomal reformation proteins[J]. Nature Cell Biology, 2023, 25(5): 685-698.

[4] Zhang K, Chowdary P D, Cui B. Visualizing directional Rab7 and TrkA cotrafficking in axons by pTIRF microscopy[J]. Methods in Molecular Biology, 2015, 1298: 319-329.

[5] Badwelan M, Muaddi H, Ahmed A, et al. Oral squamous cell carcinoma and concomitant primary tumors, what do we know? A review of the literature[J]. Current Oncology, 2023, 30(4): 3721-3734.

[6] Tan Y, Wang Z, Xu M, et al. Oral squamous cell carcinomas: state of the field and emerging directions[J]. International Journal of Oral Science, 2023, 15(1): 44.

[7] Gan M, Liu N, Li W, et al. Metabolic targeting of regulatory T cells in oral squamous cell carcinoma: new horizons in immunotherapy[J]. Molecular Cancer, 2024, 23(1): 273.

[8] Arora R, Cao C, Kumar M, et al. Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response[J]. Nature Communications, 2023, 14(1): 5029.

[9] Zhou J, Hu Z, Wang L, et al. Tumor-colonized Streptococcus mutans metabolically reprograms tumor microenvironment and promotes oral squamous cell carcinoma[J]. Microbiome, 2024, 12(1): 193.

[10] Dong L, Hu S, Li X, et al. SPP1+ TAM regulates the metastatic colonization of CXCR4+ metastasis-associated tumor cells by remodeling the lymph node microenvironment[J]. Advanced Science, 2024, 11(44): e2400524.

[11] Sun J, Tang Q, Yu S, et al. F. nucleatum facilitates oral squamous cell carcinoma progression via GLUT1-driven lactate production[J].

[12] Franken A, Bila M, Mechels A, et al. CD4+ T cell activation distinguishes response to anti-PD-L1+anti-CTLA4 therapy from anti-PD-L1 monotherapy[J]. Immunity, 2024, 57(3):

[13] Ju W T, Xia R H, Zhu D W, et al. A pilot study of neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib for locally advanced resectable oral squamous cell carcinoma[J]. Nature Communications, 2022, 13 (1): 5378.

[14] Tang S, Wang Q, Wang Z, et al. NSD1 mutation status determines metabolic inhibitor sensitivity in head and neck squamous cell carcinomas by regulating mitochondrial respiration[J]. The Journal of Pathology, 2025, 266(3): 306-321.

[15] Chen Y, Li Z, Liang J, Liu J, Hao J, Wan Q, Liu J, Luo C, Lu Z. CircRNA has_circ_0069313 induced OSCC immunity escape by miR-325-3p-Foxp3 axes in both OSCC cells and Treg cells[J]. Aging (Albany NY), 2022, 14(10): 4376-4389

[16] Shebbo S, Alateyah N, Yassin E, et al. Unravelling molecular mechanism of oral squamous cell carcinoma and genetic landscape: an insight into disease complexity, available therapies, and future considerations[J]. Frontiers in Immunology, 2025, 16: 1626243.

[17] Liu Q. Expression of RAB7A in pancreatic cancer and its clinical significance[D]. 2023.

[18] Ding N, Bai Q, Wang Z, Piao Y, Li L, Piao H, Yan G, Song Y. Artemetin targets the ABCG2/RAB7A axis to inhibit mitochondrial dysfunction in asthma[J]. Phytomedicine, 2025, 140: 156600.

[19] Zhou B, Liu J, Kang R, et al. Ferroptosis is a type of autophagy-dependent cell death[J]. Seminars in Cancer Biology, 2020, 66:89-100.

[20] Zhou C, Liang Y, Zhou L, Yan Y, Liu N, Zhang R, Huang Y, Wang M, Tang Y, Ali DW, Wang Y, Michalak M, Chen XZ, Tang J. TSPAN1 promotes autophagy flux and mediates cooperation between WNT-CTNNB1 signaling and autophagy via the MIR454-FAM83A-TSPAN1 axis in pancreatic cancer[J]. Autophagy, 2021, 17(10): 3175-3195.

[21] Zhang J Y. Research on the role and molecular mechanism of RAB7A, a downstream gene of ATF6, in regulating the progression of hepatocellular carcinoma[D]. 2024.

[22] Zhang S Y, You B, You Y W. HAX-1 participates in cisplatin resistance of nasopharyngeal carcinoma by competitively binding to Rab7a to block autophagic flux[C]2021: 456-457.

[23] Wang L L. Research on the mechanism of enhancing the sensitivity of lung cancer to gemcitabine by knocking out RAB7A based on CRISPR/Cas9 technology[D]. 2024.

[24] Xu F Y, Liu R, Ma L, et al. Network analysis of Rab7a gene in breast cancer MDA-MB-231 cells[J].2020, 46(3): 464-469-671.

[25] LLaviolette L A, Mermoud J, Calvo I A, et al. Negative regulation of EGFR signalling by the human folliculin tumour suppressor protein[J]. Nature Communications, 2017, 8(1): 15866.

[26] Stark M S, Tom L N, Boyle G M, et al. The "melanoma-enriched" microRNA miR-4731-5p acts as a tumour suppressor[J]. Oncotarget, 2016, 7(31): 49677-49687.

[27] Güleç Taşkiran A E, Hüsnügil H H, Soltani Z E, et al. Post-transcriptional regulation of Rab7a in lysosomal positioning and drug resistance in nutrient-limited cancer cells[J]. Traffic, 2024, 25(9): e12956.

[28] Kang S, Liu S, Dong X, et al. USP4 depletion-driven RAB7A ubiquitylation impairs autophagosome-lysosome fusion and aggravates periodontitis[J]. Autophagy, 2025, 21(4): 771-788.

[29] Liu H, Wu C. Charcot Marie Tooth 2B peripheral sensory neuropathy: How Rab7 mutations impact NGF signaling?[J]. International Journal of Molecular Sciences, 2017, 18(2): 324.

[30] Chen L, Hu P, Hong X, et al. Dimethyl fumarate modulates M1/M2 macrophage polarization to ameliorate periodontal destruction by increasing TUFM-mediated mitophagy[J]. International Journal of Oral Science, 2025, 17(1): 32..

[31] Rahman M A, Shaikh M H, Gupta R D, et al. Advancements in autophagy modulation for the management of oral disease: A focus on drug targets and therapeutics[J]. Biomedicines, 2024, 12(11): 2645.

[32] Deng P, Fan T, Gao P, et al. SIRT5-mediated desuccinylation of RAB7A protects against cadmium-induced Alzheimer's disease-like pathology by restoring autophagic flux[J]. Advanced Science, 2024, 11(30): e2402030.

[33] Romano R, Del Fiore V S, Saveri P, et al. Autophagy and lysosomal functionality in CMT2B fibroblasts carrying the RAB7K126R mutation[J]. Cells, 2022, 11(3): 496.

[34] Mulligan R J, Winckler B. Regulation of endosomal trafficking by Rab7 and its effectors in neurons: Clues from Charcot-Marie-Tooth 2B disease[J]. Biomolecules, 2023, 13(9): 1399.

[35] Girolimetti G, Marini F, Calvani R, et al. Circulating mitochondrial components and metabolic and inflammatory markers in Charcot-Marie-Tooth type 2B[J]. Neurobiology of Disease, 2025, 214: 107051.

[36] Bugshan A, Farooq I. Oral squamous cell carcinoma: metastasis, potentially associated malignant disorders, etiology and recent advancements in diagnosis[J]. F1000Res, 2020, 9: 229.

[37] Veerasamy V, Veeran V, Nagini S. Dysregulated PI3K/AKT signaling in oral squamous cell carcinoma: The tumor microenvironment and epigenetic modifiers as key drivers[J]. Oncology Research, 2025, 33(8): 1835-1860.

[38] Harrison MS, Hung CS, Liu TT, Christiano R, Walther TC, Burd CG. A mechanism for retromer endosomal coat complex assembly with cargo[J]. Proc Natl Acad Sci U S A, 2014, 111(1): 267-272.

[39] Glaviano A, Foo A S C, Lam H Y, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer[J]. Molecular Cancer, 2023, 22(1): 138.

[40] Zhao X W, Zhou J P, Bi Y L, et al. The role of the PI3K/AKT signaling pathway in promoting the invasion and metastasis of oral squamous cell carcinoma[J]. 2019, 38(1): 75-79.

[41] Li Y F. Research on the molecular mechanism of PKM2-mediated HMGB1 regulation of TAMs promoting the migration and invasion of oral squamous cell carcinoma[D]. 2025.

[42] Wu Y, Wang Y, Liu H, et al. Mechanism of apoptosis in oral squamous cell carcinoma promoted by cardamonin through PI3K/AKT signaling pathway[J]. Scientific Reports, 2024, 14(1): 20802.

[43] Romano R, Calcagnile M, Margiotta A et al. RAB7A regulates vimentin phosphorylation through AKT and PAK[J]. Cancers, 2021, 13(9): 2164.

[44] Zhang M, Liu S, Zhang N, et al. High expression of RAB7A is associated with poor prognosis of gastric cancer by promoting tumor invasion[J]. 2023, 43(10): 1734-1743.

[45] Bala M, CD S, TML M, et al. Expression of FGF-2/FGFR-1 in normal mucosa, salivary gland, preneoplastic, and neoplastic lesions of the oral cavity[J]. Journal of Oral Pathology & Medicine, 2018, 47(9): 821-828.

[46] Zhang X, Xu Y, Shi L, et al. FGF6 inhibits oral squamous cell carcinoma progression by regulating PI3K/AKT and MAPK pathways[J]. Scientific Reports, 2024, 14(1): 2687.

[47] Kreis J, Camuto C M, Elsner C C, et al. FGF-mediated establishment of left-right asymmetry requires Rab7 function in the dorsal mesoderm in Xenopus[J]. Frontiers in Cell and Developmental Biology, 2022, 10: 981762.

[48] Sa P, Singh P, Panda S, et al. Reversal of cisplatin resistance in oral squamous cell carcinoma by piperlongumine loaded smart nanoparticles through inhibition of Hippo-YAP signaling pathway[J]. Translational Research, 2024, 268: 101664.

[49] Hasegawa K, Fujii S, Matsumoto S, et al. YAP signaling induces PIEZO1 to promote oral squamous cell carcinoma cell proliferation[J]. The Journal of Pathology, 2021, 253(1): 80-93.

[50] Gupta A, Devi A, Kamboj M, et al. Immunohistochemical expression of PARK2 and YAP in oral epithelial dysplasia and oral squamous cell carcinoma[J]. Head and Neck Pathology, 2025, 19(1): 112-120.

[51] Wu Y, Wang S, Guo Z, et al. Hapalindole Q suppresses autophagosome-lysosome fusion by promoting YAP1 degradation via chaperon-mediated autophagy[J]. Proceedings of the National Academy of Sciences, 2024, 121(50): e2400809121.

[52] Lin J X, Xu C Y, Wu X M, et al. Rab7a-mTORC1 signaling-mediated cholesterol trafficking from the lysosome to mitochondria ameliorates hepatic lipotoxicity induced by aflatoxin B1 exposure[J]. Chemosphere, 2023, 320: 138071.

[53] Akula SM, Abrams SL, Steelman LS, Emma MR, Augello G, Cusimano A, Azzolina A, Montalto G, Cervello M, McCubrey JA. RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1 and TP53 pathways and regulatory miRs as therapeutic targets in hepatocellular carcinoma[J]. Expert Opin Ther Targets, 2019, 23(11): 915-929.

[54] Song J R. Research on the mechanism by which TTPA and Rab7A affect HBV replication through activating the mTORC1 signaling pathway[D]. 2020.

[55] Amano Y, Matsubara D, Kihara A, et al. The significance of Hippo pathway protein expression in oral squamous cell carcinoma[J]. Frontiers in Medicine, 2024, 11: 1247625.

[56] Benitha J G, Ramani P, Jayaraman S, et al. Role of PDGF-BB in oral squamous cell carcinoma through PI3/AKT/mTOR pathway: An integrated computational and Real-Time PCR-Based Approach[J]. Asian Pacific Journal of Cancer Prevention, 2026, 27(1): 109-116.

[57] Wei L J, Zhang M Y. Study on the effect of AAVC-I on inhibiting the proliferation and migration of human oral squamous cell carcinoma SCC4 and Cal27 cells through the ERK1/2/MAPK signaling pathway[J]. 2025, 30(11): 1516-1524.

[58] Rajendran P, Sekar R, Dhayasankar P S, et al. PI3K/AKT signaling pathway mediated autophagy in oral carcinoma - A comprehensive reviewJ[J]. International Journal of Medical Sciences, 2024, 21(6): 1165-1175.

[59] Hsu P C, Tsai C, Lin Y H, et al. Therapeutic targeting of apoptosis, autophagic cell death, necroptosis, pyroptosis, and ferroptosis pathways in oral squamous cell carcinoma: molecular mechanisms and potential strategies[J]. Biomedicines, 2025, 13(7): 1745.

[60] Modica G, Tejeda-Valencia L, Sauvageau E, Yasa S, Maes J, Skorobogata O, Lefrancois S. Phosphorylation on serine 72 modulates Rab7A palmitoylation and retromer recruitment[J]. J Cell Sci, 2025, 138(1): jcs262177.