Cancer stem cells (CSCs) constitute a small yet crucial subgroup in tumors, known for their capacity to self-renew, differentiate, and promote tumor growth, metastasis, and resistance to therapy. These characteristics position CSCs as significant factors in tumor recurrence and unfavorable clinical results, emphasizing their role as targets for therapy. Autophagy, an evolutionarily preserved cellular mechanism for degradation and recycling, has a complex function in cancer by aiding cell survival during stress and preserving balance by eliminating damaged organelles and proteins. Although autophagy can hinder tumor growth by reducing genomic instability, it also aids tumor advancement, particularly in harsh microenvironments, highlighting its dual characteristics. Recent research has highlighted the complex interactions between autophagy and CSCs, showing that autophagy governs CSC maintenance, boosts survival, and aids in resistance to chemotherapy and radiotherapy. On the other hand, in specific situations, autophagy may restrict CSC growth by increasing differentiation or inducing cell death. These intricate interactions offer both obstacles and possibilities for therapeutic intervention. Pharmacological modulation of autophagy, via inhibitors like chloroquine or by enhancing autophagy when advantageous, has demonstrated potential in making CSCs more responsive to standard treatments. Nonetheless, applying these strategies in clinical settings necessitates a better understanding of context-dependent autophagy dynamics and the discovery of dependable biomarkers indicating autophagic activity in CSCs. Progressing in this area might unveil novel, accurate strategies to tackle therapy resistance, lessen tumor recurrence, and ultimately enhance patient outcomes.

The most prevalent primary hepatic cancer, hepatocellular carcinoma (HCC), has a bad prognosis. HCC prevalence and related deaths have increased in recent decades. Food and Drug Administration (FDA) has licensed Sorafenib as a first-line treatment for individuals with advanced HCC. Despite this, some clinical studies indicate that a significant percentage of liver cancer patients exhibit insensitivity to sorafenib. Furthermore, the overall effectiveness of sorafenib is far from adequate, and the number of patients who benefit from therapy is low. In recent years, many researchers have focused on the mechanisms underlying sorafenib resistance. Acquired resistance to sorafenib in HCC cells has been reported to be facilitated by dysregulation of signal transducer and activator of transcription 3 (STAT3) activation, angiogenesis, autophagy, hypoxia-induced pathways, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), ferroptosis, and non-coding RNAs (ncRNAs). Recent clinical trials, including comparisons of sorafenib with immune checkpoint inhibitors like tislelizumab, have shown promise in improving patient outcomes. Additionally, combination therapies targeting complementary pathways are under investigation to overcome resistance and enhance treatment efficacy. The limitation of Sorafenib's effectiveness has been partially but not completely clarified. Furthermore, while certain regimens have demonstrated positive results, more clinical trials are required to confirm them. Future research should focus on identifying predictive biomarkers for therapy response, targeting the tumor microenvironment, and exploring novel therapeutic agents and personalized medicine strategies. A deeper understanding of these mechanisms will be essential for developing more effective therapeutic approaches and improving the prognosis of patients with advanced HCC. This article discusses strategies that may be employed to enhance the success of treatment and summarizes new research on the possible pathways that lead to sorafenib resistance.

This study explores the molecular mechanism by which sentrin/SUMO-specific protease 1 (SENP1) promotes cisplatin (Cis) resistance and tumor stem cell characteristics in colon adenocarcinoma (COAD) through deSUMOylation-mediated modification of octamer-binding transcription factor 4 (OCT4). By analyzing single-cell and transcriptome sequencing datasets, we identified key genes and regulatory pathways in both resistant and sensitive COAD cells. Malignant cells were isolated and evaluated for stemness using the infercnv package, and differential genes between Cis-resistant and -sensitive groups were identified. Machine learning algorithms highlighted essential genes, and databases predicted interaction sites between OCT4 and SENP1. In vitro experiments using enriched HCT116 stem cells revealed that SENP1 and OCT4 expression significantly elevated CD44 and CD133 levels, enhancing stemness. Functional assays showed that SENP1's deSUMOylation of OCT4 intensified Cis resistance, migration, and invasion in cisplatin-resistant cell line 116 (Cis-116) cells. In vivo, SENP1 knockdown reduced tumor growth and stem cell markers, whereas OCT4 overexpression escalated tumor metastasis and structural damage. These findings demonstrate that SENP1's modulation of OCT4 is central to COAD's resistance and stem cell properties, offering a novel target for COAD therapy.NEW & NOTEWORTHY This study uncovers the critical role of SENP1 in regulating OCT4 through deSUMOylation, driving Cis resistance and tumor stemness in COAD. Targeting this pathway may provide novel therapeutic strategies for COAD management.

Considerable evidence suggests that tumor initiation, malignancy, metastasis and recurrence occur due to emergence of cancer stem cells (CSCs). Fas binding factor 1 (FBF1) is a multifunctional protein that plays essential roles in the regulation of development and cell fate decisions. However, the function in maintaining stem cell-like properties of breast cancer remains elusive.

Tissue microarray was used to evaluate FBF1 expression. Cancer stemness assays were performed in FBF1 silencing and overexpressing cells in vitro and in a xenograft model in vivo. RNA sequencing, immunofluorescence and immunoprecipitation assays were performed to explore the underlying mechanism. Clinical expression and significance of FBF1 and stemness-associated factors were explored by analyzing datasets.

We report that FBF1 was highly expressed in breast cancer and significantly correlated with clinical progression. Silencing FBF1 in MDA-MB-231 cells restrained CSCs properties, including side population, sphere formation and migration, whereas ectopic FBF1 expression increased the side population proportion, enhanced the sphere formation ability, and promoted the expression of core stemness genes, such as SOX2, OCT4, KLF4 and NANOG, as well as facilitated metastasis of T47D breast cancer cells. Furthermore, mice bearing FBF1-overexpressed T47D xenografts had higher tumorigenic frequency and stronger metastasis potential. In addition, exploration of the underlying mechanism indicated that FBF1 binds PI3K which then activates PI3K-AKT phosphorylation cascades. Then the activated p-AKT interacts with stemness marker SOX2, elevates SOX2 and OCT4 activity, and finally forms PI3K/AKT/SOX2 axis, which mediates stem cell-like identities. Moreover, PI3K inhibitors abolished FBF1-mediated signaling pathway and diminished breast cancer stemness in vitro and in vivo. In 24 human breast cancer samples, we found a good positive correlation between the expression of FBF1 and p-AKT, as well as between FBF1 and SOX2 as determined by IHC. Clinical data showed that FBF1 expression was positively correlated with the expression of POU5F1 (OCT4), AKT1 and was negatively correlated with PTEN, which is a negative regulator of PI3K/AKT signaling.

Collectively, we identified a potential CSCs regulator and suggested a novel mechanism by which FBF1 governs cancer cell stemness. This study thus introduces an effective target for the diagnosis and treatment of breast cancer.

GRP78 (Glucose-related protein 78, BiP/HSPA5) is commonly overexpressed in cancer cells. Acting as an activator of endoplasmic reticulum stress, GRP78 is involved in the resistance of cancer cells to injury. Current evidence suggests that GRP78 plays a significant role in the radiotherapy resistance and chemotherapy resistance of cancers, which is accomplished through a variety of complex pathways. These include the promotion of tumor stemness, inhibition of apoptosis, regulation of autophagy, maintenance of tumor microenvironment homeostasis, protection of dormant cells, evasion of senescence, counteraction of autoantibodies against GRP78, facilitation of DNA damage repair, suppression of ferroptosis, and modulation of metabolic reprogramming in tumor cells. Importantly, chemoradiotherapy resistance in cancers are the main reasons for treatment failure in patients, severely affecting their survival. Investigating the mechanisms of GRP78 in tumor therapeutic resistance is essential. In this article, we review the mechanisms by which GRP78 mediates cell survival and chemoradiotherapy resistance in cancers and provide an overview of clinical trials targeting GRP78 therapy.

Cancer stem cells (CSCs) represent a distinct subset of neoplastic cells characterised by their heightened capacity for tumorigenesis. These cells are implicated in the facilitation of cancer metastasis, recurrence, and resistance to conventional therapeutic interventions. Extensive scientific research has been devoted to the identification of biomarkers and the elucidation of molecular mechanisms in order to improve targeted therapeutic approaches. Accurate identification of cancer stem cells based on biomarkers can provide a theoretical basis for drug combinations of malignant tumours. Targeted biomarker-based therapies also offer a silver lining for patients with advanced malignancies. This review aims comprehensively to consolidate the latest findings on CSCs biomarkers, targeted agents as well as biomarkers associated signalling pathways in well-established cancer types, thereby contributing to improved prognostic outcomes.

More than 90% of hepatocellular carcinoma (HCC) cases develop in the presence of fibrosis or cirrhosis, making the tumor microenvironment (TME) of HCC distinctive due to the intricate interplay between cancer-associated fibroblasts (CAFs) and cancer stem cells (CSCs), which collectively regulate HCC progression. However, the mechanisms through which CSCs orchestrate the dynamics of the tumor stroma during HCC development remain elusive. Our study unveils a significant upregulation of Sema3C in fibrotic liver, HCC tissues, peripheral blood of HCC patients, as well as sorafenib-resistant tissues and cells, with its overexpression correlating with the acquisition of stemness properties in HCC. We further identify NRP1 and ITGB1 as pivotal functional receptors of Sema3C, activating downstream AKT/Gli1/c-Myc signaling pathways to bolster HCC self-renewal and tumor initiation. Additionally, HCC cells-derived Sema3C facilitated extracellular matrix (ECM) contraction and collagen deposition in vivo, while also promoting the proliferation and activation of hepatic stellate cells (HSCs). Mechanistically, Sema3C interacted with NRP1 and ITGB1 in HSCs, activating downstream NF-kB signaling, thereby stimulating the release of IL-6 and upregulating HMGCR expression, consequently enhancing cholesterol synthesis in HSCs. Furthermore, CAF-secreted TGF-β1 activates AP1 signaling to augment Sema3C expression in HCC cells, establishing a positive feedback loop that accelerates HCC progression. Notably, blockade of Sema3C effectively inhibits tumor growth and sensitizes HCC cells to sorafenib in vivo. In sum, our findings spotlight Sema3C as a novel biomarker facilitating the crosstalk between CSCs and stroma during hepatocarcinogenesis, thereby offering a promising avenue for enhancing treatment efficacy and overcoming drug resistance in HCC.

Tissue engineering is increasingly viewed as a promising avenue for functional cartilage reconstruction. However, chondrocyte dedifferentiation during in vitro culture remains an obstacle for clinical translation of tissue engineered cartilage. Re-differentiated induction have been employed to induce dedifferentiated chondrocytes back to their original phenotype. Regrettably, these strategies have been proven to be only moderately effective.

To explore underlying mechanism, RNA transcriptome sequencing was conducted on primary chondrocytes (P0), dedifferentiated chondrocytes (P5), and redifferentiated chondrocytes (redifferentiation-induction of P5, P5.R). Based on multiple bioinformatics analysis, LGR5 was identified as a target gene. Subsequently, stable cell lines with LGR5 knocking-down and overexpression were established using P0 chondrocytes. The phenotypic changes in P1 and P5 chondrocytes with either LGR5 knockdown or overexpression were assessed to ascertain the potential influence of LGR5 dysregulation on chondrocyte phenotypes. Regulatory mechanism was then investigated using bioinformatic analysis, protein-protein docking, immunofluorescence co-localization and immunoprecipitation.

The current study found that dysregulation of LGR5 can significantly impact the dedifferentiated phenotypes of chondrocytes (P5). Upregulation of LGR5 appears to activate the PI3K/AKT signal via increasing the phosphorylation levels of AKT (p-AKT1). Moreover, the increase of p-AKT1 may stabilize β-catenin and enhance the intensity of Wnt/β-catenin signal, and help to restore the dedifferentated phenotype of chondrocytes.

LGR5 can modulate the phenotypes of chondrocytes in P5 passage through PI3K/AKT signaling pathway.

Cancer stem cells (CSCs), accounting for only a minor cell proportion (< 1%) within tumors, have profound implications in tumor initiation, metastasis, recurrence, and treatment resistance due to their inherent ability of self-renewal, multi-lineage differentiation, and tumor-initiating potential. In recent years, accumulating studies indicate that CSCs and tumor immune microenvironment act reciprocally in driving tumor progression and diminishing the efficacy of cancer therapies. Extracellular vesicles (EVs), pivotal mediators of intercellular communications, build indispensable biological connections between CSCs and immune cells. By transferring bioactive molecules, including proteins, nucleic acids, and lipids, EVs can exert mutual influence on both CSCs and immune cells. This interaction plays a significant role in reshaping the tumor immune microenvironment, creating conditions favorable for the sustenance and propagation of CSCs. Deciphering the intricate interplay between CSCs and immune cells would provide valuable insights into the mechanisms of CSCs being more susceptible to immune escape. This review will highlight the EV-mediated communications between CSCs and each immune cell lineage in the tumor microenvironment and explore potential therapeutic opportunities.

Metabolic dysfunction-associated steatohepatitis (MASH) is the progressed version of metabolic dysfunction-associated steatotic liver disease (MASLD) characterized by inflammation and fibrosis, but also a pathophysiological "hub" that favors the emergence of liver malignancies. Current research efforts aim to identify risk factors, discover disease biomarkers, and aid patient stratification in the context of MASH-induced hepatocellular carcinoma (HCC), the most prevalent cancer among MASLD patients. To investigate the tumorigenic transition in MASH-induced HCC, researchers predominantly exploit preclinical animal-based MASH models and studies based on archived human biopsies and clinical trials. Recapitulating the immune response during tumor development and progression is vital to obtain mechanistic insights into MASH-induced HCC. Notably, the advanced complexity behind MASLD and MASH pathogenesis shifted the research focus towards innate immunity, a fundamental element of the hepatic immune niche that is usually altered robustly in the course of liver disease. During the last few years, however, there has been an increasing interest for deciphering the role of adaptive immunity in MASH-induced HCC, particularly regarding the functions of the various T cell populations. To effectively understand the specific role of T cells in MASH-induced HCC development, scientists should urgently fill the current knowledge gaps in this field. Pinpointing the metabolic signature, sketching the immune landscape, and characterizing the cellular interactions and dynamics of the specific T cells within the MASH-HCC liver are essential to unravel the mechanisms that adaptive immunity exploits to enable the emergence and progression of this cancer. To this end, our review aims to summarize the current state of research regarding the T cell functions linked to MASH-induced HCC.

Sorafenib is currently the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Nevertheless, sorafenib resistance remains a huge challenge in the clinic. Therefore, it is urgent to elucidate the mechanisms underlying sorafenib resistance for developing novel treatment strategies for advanced HCC. In this study, we aimed to investigate the role and mechanisms of interleukin-22 (IL-22) in sorafenib resistance in HCC.

The in vitro experiments using HCC cell lines and in vivo studies with a nude mouse model were used. Calcium staining, chromatin immunoprecipitation, lactate dehydrogenase release and luciferase reporter assays were employed to explore the expression and roles of IL-22, STAT3 and CD155 in sorafenib resistance.

Our clinical results demonstrated a significant correlation between elevated IL-22 expression and poor prognosis in HCC. Analysis of transcriptomic data from the phase-3 STORM-trial (BIOSTORM) suggested that STAT3 signaling activation and natural killer (NK) cell infiltration may associate sorafenib responses. STAT3 signaling could be activated by IL-22 administration in HCC cells, and then enhanced sorafenib resistance in HCC cells by promoting cell proliferation and reducing apoptosis in vitro and in vivo. Further, we found IL-22/STAT3 axis can transcriptionally upregulate CD155 expression in HCC cells, which could significantly reduce NK cell-mediated HCC cell lysis in a co-culture system.

Collectively, IL-22 could contribute to sorafenib resistance in HCC by activating STAT3/CD155 signaling axis to decrease the sensitivities of tumor cells to sorafenib-mediated direct cytotoxicity and NK cell-mediated lysis. These findings deepen the understanding of how sorafenib resistance develops in HCC in terms of IL-22/STAT3 signaling pathway, and provide potential targets to overcome sorafenib resistance in patients with advanced HCC.

Non-alcoholic fatty liver disease is a chronic liver abnormality that exhibits high variability and can lead to liver cancer in advanced stages. Hepatic ablation of SIRT6 results in fatty liver disease, yet the potential mechanism of SIRT6 deficiency, particularly in relation to downstream mediators for NAFLD, remains elusive. Here we identify Serpina12 as a key gene regulated by Sirt6 that plays a crucial function in energy homeostasis. Specifically, Sirt6 suppresses Serpina12 expression through histone deacetylation at its promoter region, after which the transcription factor, Cebpα, binds to and regulates its expression. Sirt6 deficiency results in an increased expression of Serpina12 in hepatocytes, which enhances insulin signaling and promotes lipid accumulation. Importantly, CRISPR-Cas9 mediated Serpina12 knockout in the liver ameliorated fatty liver disease caused by Sirt6 ablation. Finally, we demonstrate that Sirt6 functions as a tumor suppressor in the liver, and consequently, deletion of Sirt6 in the liver leads to not only the spontaneous development of tumors but also enhanced tumorigenesis in response to DEN treatment or under conditions of obesity.

Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and it predisposes to cholangiocarcinoma due to lack of effective treatment options. Recombinant adeno-associated virus (rAAV) provides a promising platform for gene therapy on such kinds of diseases. A microRNA (miRNA) let-7a has been reported to be associated with the progress of PSC but the potential therapeutic implication of inhibition of let-7a on PSC has not been evaluated.

To investigate the therapeutic effects of inhibition of a miRNA let-7a transferred by recombinant adeno-associated virus 8 (rAAV8) on a xenobiotic-induced mouse model of sclerosing cholangitis.

A xenobiotic-induced mouse model of sclerosing cholangitis was induced by 0.1% 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine (DDC) feeding for 2 wk or 6 wk. A single dose of rAAV8-mediated anti-let-7a-5p sponges or scramble control was injected in vivo into mice onset of DDC feeding. Upon sacrifice, the liver and the serum were collected from each mouse. The hepatobiliary injuries, hepatic inflammation and fibrosis were evaluated. The targets of let-7a-5p and downstream molecule NF-κB were detected using Western blot.

rAAV8-mediated anti-let-7a-5p sponges can depress the expression of let-7a-5p in mice after DDC feeding for 2 wk or 6 wk. The reduced expression of let-7a-5p can alleviate hepato-biliary injuries indicated by serum markers, and prevent the proliferation of cholangiocytes and biliary fibrosis. Furthermore, inhibition of let-7a mediated by rAAV8 can increase the expression of potential target molecules such as suppressor of cytokine signaling 1 and Dectin1, which consequently inhibit of NF-κB-mediated hepatic inflammation.

Our study demonstrates that a rAAV8 vector designed for liver-specific inhibition of let-7a-5p can potently ameliorate symptoms in a xenobiotic-induced mouse model of sclerosing cholangitis, which provides a possible clinical translation of PSC of human.

Tumor lineage plasticity, considered a hallmark of cancer, denotes the phenomenon in which tumor cells co-opt developmental pathways to attain cellular plasticity, enabling them to evade targeted therapeutic interventions. However, the underlying molecular events remain largely elusive. Our recent study identified CD133/Prom1 in hepatocellular carcinoma (HCC) tumors to mark proliferative tumor-propagating cells with cancer stem cell-like properties, that follow a dedifferentiation trajectory towards a more embryonic state. Here we show SPINK1 to strongly associate with CD133 + HCC, and tumor dedifferentiation. Enhanced transcriptional activity of SPINK1 is mediated by promoter binding of ELF3, which like CD133, is found to increase following 5-FU and cisplatin treatment; while targeted depletion of CD133 will reduce both ELF3 and SPINK1. Functionally, SPINK1 overexpression promotes tumor initiation, self-renewal, and chemoresistance by driving a deregulated EGFR-ERK-CDK4/6-E2F2 signaling axis to induce dedifferentiation of HCC cells into their ancestral lineages. Depleting SPINK1 function by neutralizing antibody treatment or in vivo lentivirus-mediated Spink1 knockdown dampens HCC cancer growth and their ability to resist chemotherapy. Targeting oncofetal SPINK1 may represent a promising therapeutic option for HCC treatment.

Hepatocellular carcinoma (HCC) is a heterogeneous and aggressive liver cancer that presents limited treatment options. Despite being the standard therapy for advanced HCC, sorafenib frequently encounters resistance, emphasizing the need to uncover the underlying mechanisms and develop effective treatments. This comprehensive review highlights the crucial interplay between the tumor microenvironment, cancer stem cells (CSCs), and epithelial-mesenchymal transition (EMT) in the context of sorafenib resistance. The tumor microenvironment, encompassing hypoxia, immune cells, stromal cells, and exosomes, exerts a significant impact on HCC progression and therapy response. Hypoxic conditions and immune cell infiltration create an immunosuppressive milieu, shielding tumor cells from immune surveillance and hindering therapeutic efficacy. Additionally, the presence of CSCs emerges as a prominent contributor to sorafenib resistance, with CD133+ CSCs implicated in drug resistance and tumor initiation. Moreover, CSCs undergo EMT, a process intimately linked to tumor progression, CSC activation, and further promotion of sorafenib resistance, metastasis, and tumor-initiating capacity. Elucidating the correlation between the tumor microenvironment, CSCs, and sorafenib resistance holds paramount importance in the quest to develop reliable biomarkers capable of predicting therapeutic response. Novel therapeutic strategies must consider the influence of the tumor microenvironment and CSC activation to effectively overcome sorafenib resistance in HCC.

The posttranslational modifications (PTMs) of proteins, as critical mechanisms for protein regulation, are well known to enhance the functional diversity of the proteome and dramatically participate in complicated biological processes. Recent efforts in the field of cancer biology have illustrated the extensive landscape of PTMs and their crosstalk with a wide range of pro-tumorigenic signaling pathways that decisively contribute to neoplastic transformation, tumor recurrence, and resistance to oncotherapy. Cancer stemness is an emerging concept that maintains the ability of tumor cells to self-renew and differentiate and has been recognized as the root of cancer development and therapy resistance. In recent years, the PTM profile for modulating the stemness of various tumor types has been identified. This breakthrough has shed light on the underlying mechanisms by which protein PTMs maintain cancer stemness, initiate tumor relapse, and confer resistance to oncotherapies. This review focuses on the latest knowledge of protein PTMs in reprogramming the stemness of gastrointestinal (GI) cancer. A deeper understanding of abnormal PTMs in specific proteins or signaling pathways provides an opportunity to specifically target cancer stem cells and highlights the clinical relevance of PTMs as potential biomarkers and therapeutic targets for patients with GI malignancies.

The emergence of drug resistance and metastasis has long been a difficult problem for cancer treatment. Recent studies have shown that cancer stem cell populations are key factors in the regulation of cancer aggressiveness, relapse and drug resistance. Cancer stem cell (CSC) populations are highly plastic and self-renewing, giving them unique metabolic, metastatic, and chemotherapy resistance properties. N6-methyladenosine (m6A) is the most abundant internal modification of mRNA and is involved in a variety of cell growth and development processes, including RNA transcription, alternative splicing, degradation, and translation. It has also been linked to the development of various cancers. At present, the important role of m6A in tumour progression is gradually attracting attention, especially in the tumour stemness regulation process. Abnormal m6A modifications regulate tumour metastasis, recurrence and drug resistance. This paper aims to explore the regulatory mechanism of m6A in CSCs and clinical therapy, clarify its regulatory network, and provide theoretical guidance for the development of clinical targets and improvement of therapeutic effects.