Mitochondria-Modulating Liposomes Reverse Radio-Resistance for Colorectal Cancer.

Complete remission of colorectal cancer (CRC) is still unachievable in the majority of patients by common fractionated radiotherapy, leaving risks of tumor metastasis and recurrence. Herein, clinical CRC samples demonstrated a difference in the phosphorylation of translation initiation factor eIF2α (p-eIF2α) and the activating transcription factor 4 (ATF4), whose increased expression by initial X-ray irradiation led to the resistance to subsequent radiotherapy. The underlying mechanism is studied in radio-resistant CT26 cells, revealing that the incomplete mitochondrial outer membrane permeabilization (iMOMP) triggered by X-ray irradiation is key for the elevated expression of p-eIF2α and ATF4, and therefore radio-resistance. This finding guided to discover that metformin and 2-DG are synergistic in reversing radio resistance by inhibiting p-eIF2α and ATF4. Liposomes loaded with metformin and 2-DG (M/D-Lipo) are thus prepared for enhancing fractionated radiotherapy of CRC, which achieved satisfactory therapeutic efficacy in both local and metastatic CRC tumors by reversing radio-resistance and preventing T lymphocyte exhaustion.

Regulation of Angiogenesis by Non-Coding RNAs in Cancer.

Non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs, have been identified as crucial regulators of various biological processes through epigenetic regulation, transcriptional regulation, and post-transcriptional regulation. Growing evidence suggests that dysregulation and activation of non-coding RNAs are closely associated with tumor angiogenesis, a process essential for tumor growth and metastasis and a major contributor to cancer-related mortality. Therefore, understanding the molecular mechanisms underlying tumor angiogenesis is of utmost importance. Numerous studies have documented the involvement of different types of non-coding RNAs in the regulation of angiogenesis. This review provides an overview of how non-coding RNAs regulate tumor angiogenesis. Additionally, we discuss emerging strategies that exploit non-coding RNAs for anti-angiogenic therapy in cancer treatment. Ultimately, this review underscores the crucial role played by non-coding RNAs in tumor angiogenesis and highlights their potential as therapeutic targets for anti-angiogenic interventions against cancer.

A Polymeric Hydrogel to Eliminate Programmed Death-Ligand 1 for Enhanced Tumor Radio-Immunotherapy.

Programmed death-ligand 1 (PD-L1) is a specialized shield on tumor cells that evades the immune system. Even inhibited by PD-L1 antibodies, a cycling process constantly transports PD-L1 from inside to outside of cells, facilitating the renewal and replenishment of PD-L1 on the cancer cell membrane. Herein, we develop a sodium alginate hydrogel consisting of elesclomol-Cu and galactose to induce persistent cuproptosis, leading to the reduction of PD-L1 for radio-immunotherapy of colon tumors. First, a prefabricated hydrogel is synthesized by immobilizing elesclomol onto a sodium alginate saccharide chain through the coordination with bivalent copper ions (Cu2+), followed by incorporation of galactose. After implantation into the tumors, this prefabricated hydrogel can be further cross-linked in the presence of physiological calcium ions (Ca2+), resulting in the formation of a hydrogel with controlled release of elesclomol-Cu2+ (ES-Cu) and galactose. The hydrogel effectively induces the oligomerization of DLAT and cuproptosis in colorectal cancer cells. Interestingly, radiation-induced PD-L1 upregulation is abrogated in the presence of the hydrogel, releasing ES-Cu and galactose. Consequently, the sensitization of tumor to radiotherapy and immunotherapy is significantly improved, further prolonging the survival of tumor-bearing mice in both local and metastatic tumors. Our study introduces an approach that combines cuproptosis with immunotherapy and radiotherapy.

Improved prognostic prediction model for liver cancer based on biomarker data screened by combined methods.

Liver cancer is a common cause of death from cancer in the population, with the 4th highest mortality rate from cancer worldwide. The high recurrence rate of hepatocellular carcinoma after surgery is an important cause of high mortality among patients. In this paper, based on eight scheduled core markers of liver cancer, an improved feature screening algorithm was proposed based on the analysis of the basic principles of the random forest algorithm, and the system was finally applied to liver cancer prognosis prediction to improve the prediction of biomarkers for liver cancer recurrence, and the impact of different algorithmic strategies on the prediction accuracy was compared and analyzed. The results showed that the improved feature screening algorithm was able to reduce the feature set by about 50% while ensuring that the prediction accuracy was reduced within 2%.

TIF1γ inhibits lung adenocarcinoma EMT and metastasis by interacting with the TAF15/TBP complex.

The molecular underpinnings of lung adenocarcinoma (LUAD) metastasis remain poorly defined. Here, using human LUAD cell lines, we find that transcriptional intermediary factor 1 γ (TIF1γ) binds to TATA box binding protein (TBP) in competition with TBP-associated factor 15 (TAF15) and impedes TAF15/TBP-mediated interleukin 6 (IL-6) transactivation. TIF1γ modifies TAF15 through multi-mono-ubiquitylation and drives nuclear export of TAF15. Functionally, TAF15 accelerates epithelial-mesenchymal transition (EMT) and metastasis of LUAD cells, acting in just the opposite way as TIF1γ. Low TIF1γ or high TAF15 expression levels are shown in metastatic LUAD specimens and correlate with poor survival of individuals with LUAD. Our findings suggest that the TAF15/TBP complex is required for IL-6 activation-induced EMT and invasion, which are inhibited by TIF1γ. This study highlights the crucial interaction between TIF1γ and the TAF15/TBP complex for regulating EMT and metastasis in LUAD.

RNA demethylase ALKBH5 inhibits TGF-ß-induced EMT by regulating TGF-ß/SMAD signaling in non-small cell lung cancer.

AlkB homolog 5 (ALKBH5) has been revealed as a key RNA N6 -methyladenosine (m6 A) demethylase that is implicated in development and diseases. However, the function of ALKBH5 in TGF-ß-induced epithelial-mesenchymal transition (EMT) and tumor metastasis of non-small-cell lung cancer (NSCLC) remains unknown. Here, we firstly show that ALKBH5 expression is significantly reduced in metastatic NSCLC. ALKBH5 overexpression inhibits TGF-ß-induced EMT and invasion of NSCLC cells, whereas ALKBH5 knockdown promotes the corresponding phenotypes. ALKBH5 overexpression suppresses TGF-ß-stimulated NSCLC cell metastasis in vivo. ALKBH5 overexpression decreases the expression and mRNA stability of TGFßR2 and SMAD3 but increases those of SMAD6, while ALKBH5 knockdown causes the opposite results. Importantly, ALKBH5 overexpression or knockdown leads respectively to an attenuated or augmented phosphorylation of SMAD3, an indispensable downstream effector that activates TGF-ß/SMAD signaling. Moreover, m6 A-binding proteins YTHDF1/3 promotes TGFßR2 and SMAD3 expression, and YTHDF2 inhibits SMAD6 expression. YTHDF1/2/3 facilitates TGF-ß-stimulated EMT and invasion of NSCLC cells. Mechanistically, ALKBH5 affects TGFßR2, SMAD3 and SMAD6 expression and mRNA stability by erasing m6 A modification in NSCLC cells. ALKBH5 weakens YTHDF1/3-mediated TGFßR2 and SMAD3 mRNA stabilization, and abolishes YTHDF2-mediated SMAD6 mRNA degradation, supporting the notion that ALKBH5 inhibits TGF-ß-induced EMT and invasion of NSCLC cells via YTHD1/2/3-mediated mechanism. Taken together, our findings highlight an important role of ALKBH5 in regulating TGF-ß/SMAD signaling, and establish a mechanistic interaction of ALKBH5 with TGFßR2/SMAD3/SMAD6 for controlling TGF-ß-induced EMT in NSCLCs.

Quaking 5 suppresses TGF-ß-induced EMT and cell invasion in lung adenocarcinoma.

Quaking (QKI) proteins belong to the signal transduction and activation of RNA (STAR) family of RNA-binding proteins that have multiple functions in RNA biology. Here, we show that QKI-5 is dramatically decreased in metastatic lung adenocarcinoma (LUAD). QKI-5 overexpression inhibits TGF-ß-induced epithelial-mesenchymal transition (EMT) and invasion, whereas QKI-5 knockdown has the opposite effect. QKI-5 overexpression and silencing suppresses and promotes TGF-ß-stimulated metastasis in vivo, respectively. QKI-5 inhibits TGF-ß-induced EMT and invasion in a TGFßR1-dependent manner. KLF6 knockdown increases TGFßR1 expression and promotes TGF-ß-induced EMT, which is partly abrogated by QKI-5 overexpression. Mechanistically, QKI-5 directly interacts with the TGFßR1 3' UTR and causes post-transcriptional degradation of TGFßR1 mRNA, thereby inhibiting TGF-ß-induced SMAD3 phosphorylation and TGF-ß/SMAD signaling. QKI-5 is positively regulated by KLF6 at the transcriptional level. In LUAD tissues, KLF6 is lowly expressed and positively correlated with QKI-5 expression, while TGFßR1 expression is up-regulated and inversely correlated with QKI-5 expression. We reveal a novel mechanism by which KLF6 transcriptionally regulates QKI-5 and suggest that targeting the KLF6/QKI-5/TGFßR1 axis is a promising targeting strategy for metastatic LUAD.

MYOCD and SMAD3/SMAD4 form a positive feedback loop and drive TGF-ß-induced epithelial-mesenchymal transition in non-small cell lung cancer.

Myocardin (MYOCD) promotes Smad3-mediated transforming growth factor-ß (TGF-ß) signaling in mouse fibroblast cells. Our previous studies show that TGF-ß/SMADs signaling activation enhances epithelial-mesenchymal transition (EMT) in human non-small cell lung cancer (NSCLC) cells. However, whether and how MYOCD contributes to TGF-ß-induced EMT of NSCLC cells are poorly elucidated. Here, we found that TGF-ß-induced EMT was accompanied by increased MYOCD expression. Interestingly, MYOCD overexpression augmented EMT and invasion of NSCLC cells induced by TGF-ß, whereas knockdown of MYOCD expression attenuated these effects. Overexpression and knockdown of MYOCD resulted in the upregulation and downregulation of TGF-ß-induced Snail mRNA, respectively. Moreover, MYOCD overexpression promoted TGF-ß-stimulated NSCLC cell metastasis in vivo. MYOCD was highly expressed and positively correlated with Snail in metastatic NSCLC tissues. Mechanistically, MYOCD directly interacted with SMAD3 and sustained the formation of TGF-ß-induced nuclear SMAD3/SMAD4 complex, facilitating TGF-ß/SMAD3-induced transactivation of Snail. Importantly, MYOCD was transcriptionally activated by TGF-ß-induced SMAD3/SMAD4 complex and CRISPR/Cas9-mediated silencing of SMAD3/SMAD4 led to a reduction in MYOCD mRNA expression. Taken together, our findings indicate that MYOCD promotes TGF-ß-induced EMT and metastasis of NSCLC and identify a positive feedback loop between MYOCD and SMAD3/SMAD4 driving TGF-ß-induced EMT.

Circular RNA hsa_circ_0008305 (circPTK2) inhibits TGF-ß-induced epithelial-mesenchymal transition and metastasis by controlling TIF1γ in non-small cell lung cancer.

BACKGROUND: TGF-ß promotes tumor invasion and metastasis through inducing epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC). Circular RNAs (circRNAs) are recognized as functional non-coding RNAs involved in human cancers. However, whether and how circRNAs contribute to TGF-ß-induced EMT and metastasis in NSCLC remain vague. Here, we investigated the regulation and function of Circular RNA hsa_circ_0008305 (circPTK2) in TGF-ß-induced EMT and tumor metastasis, as well as a link between circPTK2 and transcriptional intermediary factor 1 γ (TIF1γ) in NSCLC. METHODS: Circular RNAs were determined by human circRNA Array analysis, real-time quantitative reverse transcriptase PCR and northern blot. Luciferase reporter, RNA-binding protein immunoprecipitation (RIP), RNA pull-down and fluorescence in situ hybridization (FISH) assays were employed to test the interaction between circPTK2 and miR-429/miR-200b-3p. Ectopic overexpression and siRNA-mediated knockdown of circPTK2, TGF-ß-induced EMT, Transwell migration and invasion in vitro, and in vivo experiment of metastasis were used to evaluate the function of circPTK2. Transcription and prognosis analyses were done in public databases. RESULTS: CircPTK2 and TIF1γ were significantly down-regulated in NSCLC cells undergoing EMT induced by TGF-ß. CircPTK2 overexpression augmented TIF1γ expression, inhibited TGF-ß-induced EMT and NSCLC cell invasion, whereas circPTK2 knockdown had the opposite effects. CircPTK2 functions as a sponge of miR-429/miR-200b-3p, and miR-429/miR-200b-3p promote TGF-ß-induced EMT and NSCLC cell invasion by targeting TIF1γ. CircPTK2 overexpression inhibited the invasion-promoting phenotype of endogenous miR-429/miR-200b-3p in NSCLC cells in response to TGF-ß. CircPTK2 overexpression significantly decreased the expression of Snail, an important downstream transcriptional activator of TGF-ß/Smad signaling. In an in vivo experiment of metastasis, circPTK2 overexpression suppressed NSCLC cell metastasis. Moreover, circPTK2 expression was dramatically down-regulated and positively correlated with TIF1γ expression in human NSCLC tissues. Especially, circPTK2 was significantly lower in metastatic NSCLC tissues than non-metastatic counterparts. CONCLUSION: Our findings show that circPTK2 (hsa_circ_0008305) inhibits TGF-ß-induced EMT and metastasis by controlling TIF1γ in NSCLC, revealing a novel mechanism by which circRNA regulates TGF-ß-induced EMT and tumor metastasis, and suggesting that circPTK2 overexpression could provide a therapeutic strategy for advanced NSCLC.

Long non-coding RNA XIST promotes TGF-ß-induced epithelial-mesenchymal transition by regulating miR-367/141-ZEB2 axis in non-small-cell lung cancer.

Growing evidence shows that lncRNA XIST functions as an oncogene accelerating tumor progression. Transforming growth factor ß (TGF-ß)-induced epithelial-mesenchymal transition (EMT) plays a key role in tumor metastasis. However, it is still unclear whether lncRNA XIST is implicated in TGF-ß-induced EMT and influences cell invasion and metastasis in non-small-cell lung cancer (NSCLC). Here, we observed increased expression of lncRNA XIST and ZEB2 mRNA in metastatic NSCLC tissues. Knockdown of lncRNA XIST inhibited ZEB2 expression, and repressed TGF-ß-induced EMT and NSCLC cell migration and invasion. Being in consistent with the in vitro findings, the in vivo experiment of metastasis showed that knockdown of lncRNA XIST inhibited pulmonary metastasis of NSCLC cells in mice. In addition, knockdown of ZEB2 expression can inhibit TGF-ß-induced EMT and NSCLC cell migration and invasion. Mechanistically, lncRNA XIST and ZEB2 were targets of miR-367 and miR-141. Furthermore, both miR-367 and miR-141 expression can be upregulated by knockdown of lncRNA XIST. Taken together, our study reveals that lncRNA XIST can promote TGF-ß-induced EMT and cell invasion and metastasis by regulating miR-367/miR-141-ZEB2 axis in NSCLC.