bims-exocan 2023-07-09 papers

bims-exocan

Biomed News

on Exosomes roles in cancer

Issue of 2023‒07‒09
thirteen papers selected by
Muhammad Rizwan
COMSATS University

Impact of exosome therapy on pancreatic cancer and its progression.
Current Strategies for Exosome Cargo Loading and Targeting Delivery.
A comprehensive review on the composition, biogenesis, purification, and multifunctional role of exosome as delivery vehicles for cancer therapy.
Therapeutic Signature of Stem Cell Derivative Exosomes in Oral Cancer: A Scoping Review.
Low-dose aspirin can inhibit exosomal release induced by radiotherapy in breast cancer and attenuate its inhibitory effect on NK cell proliferation.
The Role of Extracellular Vesicles in Colorectal Cancer.
Extracellular vesicles carrying miR-6836 derived from resistant tumor cells transfer cisplatin resistance of epithelial ovarian cancer via DLG2-YAP1 signaling pathway.
Establishment and Evaluation of Exosomes-Related Gene Risk Model in Hepatocellular Carcinoma.
Evaluation of exosomes encapsulated recombinant Interleukin-29 for its in vitro anticancer studies.
Emerging diversity in extracellular vesicles and their roles in cancer.
Exosomal PIK3CB promotes PD-L1 expression and malignant transformation in esophageal squamous cell carcinoma.
Emerging chemical engineering of exosomes as "bioscaffolds" in diagnostics and therapeutics.
CAF-derived exosomal lncRNA FAL1 promotes chemoresistance to oxaliplatin by regulating autophagy in colorectal cancer.

Med Oncol. 2023 Jul 05. 40(8): 225

Impact of exosome therapy on pancreatic cancer and its progression.

Mohamed El-Tanani, Hamdi Nsairat, Ismail I Matalka, Alaa A A Aljabali, Vijay Mishra, Yachana Mishra, Gowhar A Naikoo, Sai Raghuveer Chava, Nitin B Charbe, Murtaza M Tambuwala.

  Pancreatic cancer, one of the most aggressive tumors, has a dismal prognosis because of the low rates of early identification, fast progression, difficulties following surgery, and the ineffectiveness of current oncologic therapies. There are no imaging techniques or biomarkers that can accurately identify, categorize, or predict the biological behavior of this tumor. Exosomes are extracellular vesicles that play a crucial rule in the progression, metastasis, and chemoresistance of pancreatic cancer. They have been verified to be potential biomarkers for pancreatic cancer management. Studying the role of exosomes in pancreatic cancer is substantial. Exosomes are secreted by most eukaryotic cells and participated in intercellular communication. The components of exosomes, including proteins, DNA, mRNA, microRNA, long non-coding RNA, circular RNA, etc., play a crucial role in regulating tumor growth, metastasis, and angiogenesis in the process of cancer development, and can be used as a prognostic marker and/or grading basis for tumor patients. Hereby, in this concise review, we intend to summarize exosomes components and isolation, exosome secretion, function, importance of exosomes in the progression of pancreatic cancer and exosomal miRNAs as possible pancreatic cancer biomarkers. Finally, the application potential of exosomes in the treatment of pancreatic cancer, which provides theoretical supports for using exosomes to serve precise tumor treatment in the clinic, will be discussed.

Keywords:  Biomarkers; Exosomes; Folfirinox; Gemcitabine; Intercellular communication; Pancreatic cancer

DOI:  https://doi.org/10.1007/s12032-023-02101-x
Cells. 2023 May 17. pii: 1416. [Epub ahead of print]12(10):

Current Strategies for Exosome Cargo Loading and Targeting Delivery.

Haifeng Zeng, Shaoshen Guo, Xuancheng Ren, Zhenkun Wu, Shuwen Liu, Xingang Yao.

  Extracellular vesicles (EVs) such as ectosomes and exosomes have gained attention as promising natural carriers for drug delivery. Exosomes, which range from 30 to 100 nm in diameter, possess a lipid bilayer and are secreted by various cells. Due to their high biocompatibility, stability, and low immunogenicity, exosomes are favored as cargo carriers. The lipid bilayer membrane of exosomes also offers protection against cargo degradation, making them a desirable candidate for drug delivery. However, loading cargo into exosomes remains to be a challenge. Despite various strategies such as incubation, electroporation, sonication, extrusion, freeze-thaw cycling, and transfection that have been developed to facilitate cargo loading, inadequate efficiency still persists. This review offers an overview of current cargo delivery strategies using exosomes and summarizes recent approaches for loading small-molecule, nucleic acid, and protein drugs into exosomes. With insights from these studies, we provide ideas for more efficient and effective delivery of drug molecules by using exosomes.

Keywords:  cargo loading; exosomes; extracellular vesicles; targeting delivery

DOI:  https://doi.org/10.3390/cells12101416
Biomed Pharmacother. 2023 Jun 29. pii: S0753-3322(23)00878-8. [Epub ahead of print]165 115087

A comprehensive review on the composition, biogenesis, purification, and multifunctional role of exosome as delivery vehicles for cancer therapy.

Jian Li, Ye Zhang, Pei-Yu Dong, Guo-Ming Yang, Sangiliyandi Gurunathan.

  All forms of life produce nanosized extracellular vesicles called exosomes, which are enclosed in lipid bilayer membranes. Exosomes engage in cell-to-cell communication and participate in a variety of physiological and pathological processes. Exosomes function via their bioactive components, which are delivered to target cells in the form of proteins, nucleic acids, and lipids. Exosomes function as drug delivery vehicles due to their unique properties of innate stability, low immunogenicity, biocompatibility, biodistribution, accumulation in desired tissues, low toxicity in normal tissues, and the stimulation of anti-cancer immune responses, and penetration capacity into distance organs. Exosomes mediate cellular communications by delivering various bioactive molecules including oncogenes, oncomiRs, proteins, specific DNA, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), and circular RNA (circRNA). These bioactive substances can be transferred to change the transcriptome of target cells and influence tumor-related signaling pathways. After considering all of the available literature, in this review we discuss the biogenesis, composition, production, and purification of exosomes. We briefly review exosome isolation and purification techniques. We explore great-length exosomes as a mechanism for delivering a variety of substances, including proteins, nucleic acids, small chemicals, and chemotherapeutic drugs. We also talk about the benefits and drawbacks of exosomes. This review concludes with a discussion future perspective and challenges. We hope that this review will provide us a better understanding of the current state of nanomedicine and exosome applications in biomedicine.

Keywords:  Biogenesis; Biological barriers; Cancer; Drug delivery; Exosome; Extracellular vesicle; Isolation

DOI:  https://doi.org/10.1016/j.biopha.2023.115087
Cureus. 2023 Jun;15(6): e39957

Therapeutic Signature of Stem Cell Derivative Exosomes in Oral Cancer: A Scoping Review.

Aanuja Singha, Magesh K T, Ramya Mahalingam, Sathya Kumar M, Aravindhan R, Sivachandran A.

  Oral cancer poses a serious health challenge to the nations worldwide. India, among all the nations reported, has the largest number of oral cancer cases, which accounts for one-third of the entire population of oral cancer globally. As oral cancer is well-known for delayed diagnosis until an advanced stage, poor outcomes, and a lack of specific biomarkers for the disease and high-budget therapeutic alternatives. Stem cell derivative exosomes gained significant attention as therapeutic agents and diagnostic biomarkers in cancer biology. It's a type of extracellular vesicle, which are lipid-bilayer-enclosed vesicles of endosomal origin. They are nanosized membrane vesicles that are capable of self-renewal, unlimited proliferation, and multi-directional differential potential. Thus, they act salient in the occurrence and development of tumors. Exosomal micro-RNAs (miRNAs) are functionally related to the advancement of cancer, metastasis, and the aggressive nature of tumors with high recurrence rates. It has also been highlighted that exosomes have the potential to serve as diagnostic markers. A quick, easy, high-clarity, and confined rehabilitation method is the basic specification for large-scale usage of exosomes. The constitution of the composite transporters of exosomes is easily available by sampling biological fluids (liquid biopsies) from samples such as saliva. A liquid biopsy based on exosomes focuses on their probable usage in cancer patients' diagnosis and the determination of the outcome or course of the disease. This review explores the therapeutic prospect of stem cell-derived exosomes as intending to offer new ideas for clinical management and institute a new era of therapeutic agents for oral cancer.

Keywords:  biogenesis of exosomes; cancer drug delivery and epithelial mesenchymal transition; exosomes; oral cancer; stem cell

DOI:  https://doi.org/10.7759/cureus.39957
Cancer Med. 2023 Jul 01.

Low-dose aspirin can inhibit exosomal release induced by radiotherapy in breast cancer and attenuate its inhibitory effect on NK cell proliferation.

Li Wang, Zaoxiu Hu, Ceshi Chen, Ting Chen, Zhihong Yao, Wenhui Li, Zuozhang Yang.

  BACKGROUND: Breast cancer (BC) seriously threatens women's health. Aspirin plays a key role in the treatment and prognosis of BC.OBJECTIVE: To explore the effect of low-dose aspirin on BC radiotherapy through the mechanism of exosomes and natural killer (NK) cells.
METHODS: BC cells were injected into the left chest wall to establish a BC model in nude mice. Tumor morphology and size were observed. Immunohistochemical staining for Ki-67 was used to observe the proliferation of tumor cells. TUNEL was used to detect the apoptosis of cancer cells. Protein levels of exosomal biogenesis- and secretion-related genes (Rab 11, Rab27a, Rab27b, CD63, and Alix) were detected by Western blot. Flow cytometry was used to detect apoptosis. Transwell assays were used to detect cell migration. A clonogenic assay was used to detect cell proliferation. Exosomes of BT549 and 4T1-Luc cells were extracted and observed by electron microscopy. After the coculture of exosomes and NK cells, the activity of NK cells was detected by CCK-8.
RESULTS: The protein expression of genes related to exosomal genesis and secretion (Rab 11, Rab27a, Rab27b, CD63, and Alix) in BT549 and 4T1-Luc cells was upregulated under radiotherapy treatment. Low doses of aspirin inhibited exosome release from BT549 and 4T1-Luc cells and alleviated the inhibitory effect of BC cell exosomes on NK cell proliferation. In addition, knocking down Rab27a reduced the protein levels of exosome-related and secretion-related genes in BC cells, further enhancing the promotive effect of aspirin on NK cell proliferation, while overexpressing Rab27a had the opposite effect. Aspirin was combined at a radiotherapeutic dose of 10 Gy to enhance the radiotherapy sensitivity of radiotherapy-tolerant BC cells (BT549R and 4T1-LucR). Animal experiments have also verified that aspirin can promote the killing effect of radiotherapy on cancer cells and significantly inhibit tumor growth.
CONCLUSION: Low doses of aspirin can inhibit the release of BC exosomes induced by radiotherapy and weaken their inhibition of NK cell proliferation, promoting radiotherapy resistance.

Keywords:  aspirin; breast cancer; exosomes; natural killer cells; radiotherapy

DOI:  https://doi.org/10.1002/cam4.6274
Technol Cancer Res Treat. 2023 Jan-Dec;22:22 15330338231185008

The Role of Extracellular Vesicles in Colorectal Cancer.

Yujian Xia, Chaoran Yu, Ernest Johann Helwig, Yousheng Li.

  Extracellular vesicles (EVs) are a class of spherical vesicles that are produced by active secretion of cells and encapsulated by phospholipid bilayers. In recent years, numerous studies have shown that EVs play pivotal roles in the regulation of intercellular communication between colorectal cancer (CRC) cells and target cells, and can regulate the proliferation, metastasis, and infiltration of tumor cells by regulating the microenvironment of tumor cells. EVs carry specific molecular substances in source CRC cells and are expected to serve as new molecular markers for the detection of cancers. This review highlights the current state of research and progress of potentially incorporating EVs in the diagnosis and treatment of CRC.

Keywords:  Colorectal cancer; diagnosis; extracellular vesicles (EVs); treatment

DOI:  https://doi.org/10.1177/15330338231185008
Int J Biol Sci. 2023 ;19(10): 3099-3114

Extracellular vesicles carrying miR-6836 derived from resistant tumor cells transfer cisplatin resistance of epithelial ovarian cancer via DLG2-YAP1 signaling pathway.

Yazhu Zou, Zitong Zhao, Jingjing Wang, Liying Ma, Yi Liu, Li Sun, Yongmei Song.

  Background: Chemotherapy resistance is a significant cause for poor prognosis of epithelial ovarian cancer (EOC). However, the molecular mechanism of chemo-resistance remains unclear, and developing available therapies and effective biomarkers for resistant EOC is in urgent demand. Stemness of cancer cells directly results in chemo-resistance. Exosomal miRNAs rebuild tumor microenvironment (TME) and act as widely used clinical liquid biopsy markers. Methods: In our study, high throughput screenings and comprehensive analysis were performed to screen for miRNAs, which were both up-regulated in resistant EOC tissues and related to stemness, and miR-6836 was identified accordingly. Results: Clinically, high miR-6836 expression was closely correlated with poor chemotherapy response and survival for EOC patients. Functionally, miR-6836 promoted EOC cell cisplatin resistance by increasing stemness and suppressing apoptosis. Mechanistically, miR-6836 directly targeted DLG2 to enhance Yap1 nuclear translocation, and was regulated by TEAD1 forming the positive feedback loop: miR-6836-DLG2-Yap1-TEAD1. Furthermore, miR-6836 could be packaged into secreted exosomes in cisplatin-resistant EOC cells and exosomal miR-6836 was able to be delivered into cisplatin-sensitive EOC cells and reverse their cisplatin response. Conclusion: Our study revealed the molecular mechanisms of chemotherapy resistance, and identified miR-6836 as the possible therapeutic target and effective biopsy marker for resistant EOC.

Keywords:  Cisplatin resistance; DLG2; Extracellular vesicles; Ovarian cancer; TEAD1; YAP1; miR-6836

DOI:  https://doi.org/10.7150/ijbs.83264
Biochem Genet. 2023 Jul 05.

Establishment and Evaluation of Exosomes-Related Gene Risk Model in Hepatocellular Carcinoma.

Lin Zhu, Yan Lou, Qiyu Xiao, Ling Wang, Guodong Chen, Wenjun Yang, Tengjiao Wang.

  Hepatocellular carcinoma (HCC) is a challenging disease to evaluate in terms of prognosis, requiring close attention to the prognosis of HCC patients. Exosomes have been shown to play an important role in HCC development and have significant potential in managing HCC patient prognosis, as they are detectable in patients' blood. By using small extracellular vesicular RNA, liquid biopsies can reflect the underlying physiological and pathological status of the originating cells, providing a valuable assessment of human health. No study has explored the diagnostic value of mRNA expression changes in exosomes for liver cancer. The present study investigated establishing a risk prognosis model based on mRNA expression levels in exosomes from blood samples of liver cancer patients and evaluated its diagnostic and prognostic value, providing new targets for liver cancer detection. We obtained mRNA data from HCC patients and normal controls from the TCGA and exoRBase 2.0 databases and established a risk prognostic assessment model using exosomes-related risk genes selected through prognostic analysis and Lasso Cox analysis. The patients were divided into high-risk and low-risk groups based on median risk score values to validate the independence and evaluability of the risk score. The clinical value of the model was further analyzed using a nomograph model, and the efficacy of immunotherapy and cell-origin types of prognostic risk genes were further assessed in the high- and low-risk groups by immune checkpoint and single-cell sequencing. A total of 44 genes were found to be significantly associated with the prognosis of HCC patients. From this group, we selected six genes (CLEC3B, CYP2C9, GNA14, NQO1, NT5DC2, and S100A9) as exosomal risk genes and used them as a basis for the risk prognosis model. The clinical information of HCC patients from the TCGA and ICGC databases demonstrated that the risk prognostic score of the model established in this study was an independent prognostic factor with good robustness. When pathological stage and risk prognostic score were incorporated into the model to predict clinical outcomes, the nomograph model had the best clinical benefit. Furthermore, immune checkpoint assays and single-cell sequencing analysis suggested that exosomal risk genes were derived from different cell types and that immunotherapy in the high-risk groups could be beneficial. Our study demonstrated that the prognostic scoring model based on exosomal mRNA was highly effective. The six genes selected using the scoring model have been previously reported to be associated with the occurrence and development of liver cancer. However, this study is the first to confirm that these related genes existed in the blood exosomes, which could be used for liquid biopsy of patients with liver cancer, thereby avoiding the need for puncture diagnosis. This approach has a high value in clinical application. Through single-cell sequencing, we found that the six genes in the risk model originate from multiple cell types. This finding suggests that the exosomal characteristic molecules secreted by different types of cells in the microenvironment of liver cancer may serve as diagnostic markers.

Keywords:  Exosomes; Gene set enrichment analysis; Hepatocellular carcinoma; Prognosis; Risk model

DOI:  https://doi.org/10.1007/s10528-023-10441-6
J Biotechnol. 2023 Jun 30. pii: S0168-1656(23)00127-X. [Epub ahead of print]373 24-33

Evaluation of exosomes encapsulated recombinant Interleukin-29 for its in vitro anticancer studies.

Nao Akusa Fujimura, Seerat E Fatima, Nadeem Ahmed, Muhammad Akram, Saad Tahir, Mohsin Ahmad Khan, Imran Amirzada, Tariq Nadeem, Hamid Bashir, Kausar Malik.

  Exosomes have recently been considered ideal biotherapeutic nanocarriers that broaden the frontiers of current drug delivery systems to overcome the shortcomings associated with cytokine-based immunotherapy. Using this approach, the current study aimed to assess anti-proliferative activity of purified IL-29 and exosomes encapsulated IL-29. The IL-29+pET-28a construct was transformed into Rosetta 2(DE3) cells which was used for the large-scale production of IL-29. Exosomes isolated from H1HeLa, and SF-767 cells using Total Exosome Isolation reagent were loaded with IL-29 via sonication. Isolation of exosomes was validated using their core protein signature by western blotting and specific miRNA profiles by RT-PCR. The drug loading efficiency of exosomes derived from H1HeLa cells was higher than that of SF-767-derived exosomes. The drug release kinetics of IL-29 encapsulated exosomes exhibited stable release of the recombinant drug. Around 50% of all cancer cell lines survived when IL-29 was administered at a concentration of 20 µg/mL. A survival rate of less than 10% was observed when cells were treated with 20 µg/mL IL-29 loaded exosomes. It was concluded that IL-29 loaded exosomes had a more significant cytotoxic effect against cancer cells, which might be attributed to sustained drug release, improved half-life, superior targeting efficacy, capacity to harness endogenous intracellular trafficking pathways, and heightened biocompatibility of exosomes.

Keywords:  Cancer treatment; Exosomes; IL-29 encapsulated exosomes; Nanoparticles; Recombinant IL-29

DOI:  https://doi.org/10.1016/j.jbiotec.2023.06.008
Front Oncol. 2023 ;13 1167717

Emerging diversity in extracellular vesicles and their roles in cancer.

Ikjot S Sohal, Andrea L Kasinski.

  Extracellular vesicles have undergone a paradigm shift from being considered as 'waste bags' to being central mediators of cell-to-cell signaling in homeostasis and several pathologies including cancer. Their ubiquitous nature, ability to cross biological barriers, and dynamic regulation during changes in pathophysiological state of an individual not only makes them excellent biomarkers but also critical mediators of cancer progression. This review highlights the heterogeneity in extracellular vesicles by discussing emerging subtypes, such as migrasomes, mitovesicles, and exophers, as well as evolving components of extracellular vesicles such as the surface protein corona. The review provides a comprehensive overview of our current understanding of the role of extracellular vesicles during different stages of cancer including cancer initiation, metabolic reprogramming, extracellular matrix remodeling, angiogenesis, immune modulation, therapy resistance, and metastasis, and highlights gaps in our current knowledge of extracellular vesicle biology in cancer. We further provide a perspective on extracellular vesicle-based cancer therapeutics and challenges associated with bringing them to the clinic.

Keywords:  cancer; exophers; exosomes; extracellular vescicles; metastasis; migrasomes

DOI:  https://doi.org/10.3389/fonc.2023.1167717
Med Oncol. 2023 Jul 04. 40(8): 221

Exosomal PIK3CB promotes PD-L1 expression and malignant transformation in esophageal squamous cell carcinoma.

Wei Xu, Yang Chen, Zhi Zhang, Yuequan Jiang, Zhiqiang Wang.

  Esophageal squamous cell carcinoma (ESCC), which accounts for 90% of esophageal carcinomas, seriously endangers human health. Worse still, the 5-year overall survival of ESCC is approximately 20%. Elucidation of the potential mechanism and exploration of promising drugs for ESCC are urgently needed. In this study, a high level of exosomal PIK3CB protein was found in the plasma of ESCC patients, which might indicate a poor prognosis. Moreover, a significant Pearson's correlation was observed at the protein level between exosomal PIK3CB and exosomal PD-L1. Further study revealed that cancer cell-intrinsic and exosome-derived PIK3CB promoted the transcriptional activity of the PD-L1 promoter in ESCC cells. Moreover, treatment with exosomes with lower levels of exosomal PIK3CB decreased the protein level of the mesenchymal marker β-catenin while increasing that of the epithelial marker claudin-1, indicating the potential regulation of epithelial-mesenchymal transition. Consequently, the migratory ability and cancer stemness of ESCC cells and the growth of tumors formed by ESCC cells were decreased with the downregulation of exosomal PIK3CB. Therefore, exosomal PIK3CB plays an oncogenic role by promoting PD-L1 expression and malignant transformation in ESCC. This study may provide new insight into the inherent biological aggressiveness and the poor response to currently available therapies of ESCC. Exosomal PIK3CB may be a promising target for the diagnosis and therapy of ESCC in the future.

Keywords:  ESCC; Exosomal PD-L1; Exosomal PIK3CB; Exosome; Malignant transformation

DOI:  https://doi.org/10.1007/s12032-023-02093-8
Genes Dis. 2023 Jul;10(4): 1494-1512

Emerging chemical engineering of exosomes as "bioscaffolds" in diagnostics and therapeutics.

Jianwei Wang, Meijiao Wang, Ning Jiang, Shijia Ding, Qiling Peng, Lei Zheng.

  All cells release extracellular vesicles (EVs) as part of their normal physiology. As one of the subtypes, exosomes (EXOs) have an average size range of approximately 40 nm-160 nm in diameter. Benefiting from their inherent immunogenicity and biocompatibility, the utility of autologous EXOs has the potential for both disease diagnosis/treatment. EXOs are generally employed as "bioscaffolds" and the whole diagnostic and therapeutic effects are mainly ascribed to exogenous cargos on the EXOs, such as proteins, nucleic acids, and chemotherapeutic agents and fluorophores delivered into specific cells or tissues. Surface engineering of EXOs for cargo loadings is one of the prerequisites for EXO-mediated diagnosis/treatment. After revisiting EXO-mediated diagnosis/treatment, the most popular strategies to directly undertake loadings of exogenous cargos on EXOs include genetic and chemical engineering. Generally, genetically-engineered EXOs can be merely produced by living organisms and intrinsically face some drawbacks. However, chemical methodologies for engineered EXOs diversify cargos and extend the functions of EXOs in the diagnosis/treatment. In this review, we would like to elucidate different chemical advances on the molecular level of EXOs along with the critical design required for diagnosis/treatment. Besides, the prospects of chemical engineering on the EXOs were critically addressed. Nevertheless, the superiority of EXO-mediated diagnosis/treatment via chemical engineering remains a challenge in clinical translation and trials. Furthermore, more chemical crosslinking on the EXOs is expected to be explored. Despite substantial claims in the literature, there is currently no review to exclusively summarize the chemical engineering to EXOs for diagnosis/treatment. We envision chemical engineering of EXOs will encourage more scientists to explore more novel technologies for a wider range of biomedical applications and accelerate the successful translation of EXO-based drug "bioscaffolds" from bench to bedside.

Keywords:  Chemical engineering; Diagnostics; Exosomes; Extracellular vesicles; Theranostics; Therapeutics

DOI:  https://doi.org/10.1016/j.gendis.2022.10.020
Dig Liver Dis. 2023 Jul 01. pii: S1590-8658(23)00705-3. [Epub ahead of print]

CAF-derived exosomal lncRNA FAL1 promotes chemoresistance to oxaliplatin by regulating autophagy in colorectal cancer.

Sixian Zhu, Jie Mao, Xiaoli Zhang, Ping Wang, Yi Zhou, Jin Tong, Hui Peng, Bei Yang, Qiang Fu.

  Oxaliplatin is a widely applied anti-cancer drug in clinics for colorectal cancer (CRC) treatment. Nonetheless, the treatment efficacy is always limited by the acquisition of chemoresistance in cancer cells. The deregulation of long non-coding RNA (lncRNA) FAL1 has been implicated in the tumorigenesis and progression of different malignancies. Nevertheless, the possible contribution of lnc-FAL1 in drug resistance development of CRC has not been investigated. Here, we reported the overexpression of lnc-FAL1 in CRC samples, and elevated lnc-FAL1 levels seemed to be associated with the poor survival in CRC patients. We further demonstrated that lnc-FAL1 promoted oxaliplatin chemoresistance in both cell and animal model. Additionally, lnc-FAL1 was mainly derived from exosomes secreted by cancer associated fibroblasts (CAFs), and lnc-FAL1-containing exosomes or lnc-FAL1 overexpression significantly inhibited oxaliplatin-induced autophagy in CRC cells. Mechanistically, lnc-FAL1 acted as a scaffold for the interaction between Beclin1 and TRIM3 to promote TRIM3-dependent Beclin1 polyubiquitination and degradation, thereby suppressing oxaliplatin-induced autophagic cell death. In summary, these data imply a molecular mechanism through which CAF-derived exosomal lnc-FAL1 contributes to the acquisition of oxaliplatin resistance in CRC.

Keywords:  Autophagy; Colorectal cancer; Exosome; Oxaliplatin; lncRNA

DOI:  https://doi.org/10.1016/j.dld.2023.06.010