In lung cancer, Let-7 targets IGF-1R to induce autophagy and blocks the function of BCL2L1/BCL2/PI3K complex to induce apoptosis and pyroptosis and inhibit cell motility [88]. Let-7a targets Rictor’s mTORC2 component, inhibiting AKT/mTORC1 signaling to activate autophagy in gastric cancer [89]. Similar regulation can be observed in human placental trophoblasts, in which the expression of Let-7b was correlated with cell growth and motility. The Let-7b-mediated TGFBR1/ERK/IL-6/TNF-α cascade triggers not only apoptosis but also autophagy. Such regulation may contribute to pre-eclampsia during pregnancy [90]. In glioma, the downregulation of STAT3 was mediated by Let-7a, Let-7d, and Let-7f. Upregulation of Let-7 suppressed the expression of STAT3, resulting in the inhibition of cell proliferation and induction of autophagy and apoptosis [91]. Liang et al. identified that a set of the Let-7 family was downregulated in hepatocellular carcinoma, with different clinical correlations under a genetic profiling analysis. The expression of Let-7b and Let-7c had a better prognosis; Let-7e had a poor prognosis instead. Among them, Let-7e has been demonstrated to promote tumor growth by suppressing autophagy and apoptosis [92]. A similar strategy was used in cholangiocarcinoma. Clinical evidence showed that the expression of NUAK1 was negatively correlated with Let-7a. NUAK1-mediated cholangiocarcinoma cell motility can be suppressed by increasing Let-7a. In turn, the overexpression of Let-7a inhibited NUAK1-mediated tumor malignancy by the induction of autophagy [93]. Additionally, Let-7 can be regulated by LncRNA H19 and LIN28 in breast cancer. The expression of long non-coding RNA (lncRNA) H19 and LIN28 was correlated with breast cancer’s poor prognosis and metastasis ability. Overexpression of H19 and LIN28 increases the expression of several autophagy-related ATG markers as well as its puncta structure formation. Downregulation of Let-7 increased the transcript activity of several EMT-related genes—including Slug, Zeb1, Twist, Snail, β-catenin, and HMGA2—to modulate the metastasis of breast cancer [94]. Another lncRNA MIR99AHG, as well as its Let-7c-associated cluster, were reported to have decreased expression in lung cancer. MIR99AHG increased Let-7c, subsequently promoting autophagy via targeting mTOR, an autophagy suppressor of nucleation, and ANXA2, a negative regulator of elongation, to suppress the growth and motility of lung adenocarcinoma [95]. In view of the controversial role of autophagy in a variety of cancers, the regulation of Let-7-mediated autophagy in tumor progression could be complicated—and condition-, environment-, and tissue-specific.

Several components have been identified as triggering Let-7-mediated autophagy in cancer cells. Treating cells with recombinant capsid protein viral particle 1 (rVP1) induces autophagy to regulate the motility of macrophages [96] and ovarian cancer cells [97]. In ovarian cancer, autophagy—activated by either a canonical or a rVP1-mediated noncanonical pathway—maintains the homeostasis of the Let-7 level through SQSTM1-mediated degradation of Dicer/AGO2 inhibition of cell migration [97]. In lymphosarcoma, the expression of Let-7g/CTSB may be suppressed by ribonuclease binase to participate in apoptosis and autophagy [98].

In gastric cancer, the expression of miR-202 can be restricted by lncRNA MALAT1, resulting in the activation of autophagy, increased tumor malignancy, and an enhanced drug-resistant ability [99]. In agreement with other reports, Yang et al. showed that paclitaxel-based drug-resistant breast cancer cells express a high level of CircRNA ABCB10 and autophagy, which are correlated with clinical paclitaxel-sensitive or resistant data and negatively associated to Let-7a. Mechanistically, the Let-7a/DUSP7 axis is a downstream effector of Circ-ABCB10 resistant to paclitaxel treatment. Knockdown of Circ-ABCB10 not only increases sensitivity to paclitaxel but also decreases tumor weight [100]. Similar regulation was observed in a cisplatin-based resistance model of A549 with a high level of DICER. Overexpression of DICER induces autophagy processes and increased tumor growth and motility, in which DICER-mediated suppression of Let-7i and the PI3K/AKT/mTOR axis contributes to the autophagy activity [67]. In medulloblastoma, inhibited autophagy was found to promote tumor resistance upon cisplatin treatment. The level of Let-7f in cells was insufficient to repress HMGB1 and led to autophagy-mediated drug resistance. Overexpression of Let-7f could attenuate cisplatin’s drug resistance and induce apoptosis in medulloblastoma cells [101].

Recently, Let-7-mediated autophagy has been described as participating in glucose metabolism events. For example, Duan et al. observed that Let-7 targeted BCL-xL to induce autophagic cell death in lung cancer, indicating that Let-7 regulates mitochondria-related autophagy (mitophagy) to regulate metabolism-related events, and BCL-xL with non-apoptotic functions to induce cell death [102]. However, the underlying mechanism of Let-7-mediated autophagy in glucose metabolism that contributes to cell stress and death needs to be further elucidated. According to the above reports, several links may support the correlation between Let-7, autophagy, and glucose metabolism. In turn, Lai et al. found that—in a hypoxic environment—HIF-1α can interact with DICER to regulate miRNA processing in diverse cancer types, including colon, breast, liver, lung, and prostate cancer [103]. HIF-1α changed the glycolysis-related enzyme PDK1 level and induced autophagy-mediated proteolysis by interacting with Parkin/p62 to possess DICER, which decreased Let-7 biogenesis. Overexpression of HIF-1α reduced the levels of Let-7a, Let-7b, and Let-7d as well as its complement downstream target LIN41 and Aurora B to promote tumor metastasis [103]. However, how glycolysis participates in DICER ubiquitination and related autophagy processes has not yet been well explained. So far, Lai et al.’s study provides a possible reason for why the Let-7 level being downregulated under hypoxia is an important factor contributing to tumor microenvironment reprogramming and providing tumor cells with escape from immune surveillance. Recently, bone marrow-derived human mesenchymal stem cells (hMSCs) have been observed to have anticancer activity. Egea et al. found that Let-7f can be transactivated under hypoxia to induce autophagy in hMSCs and promote migration in tumor cells [104]. Let-7f can be regulated by TGF-β, TNF-α, IL-1β, and SDF-1α to modulate CXCR4 and MMP-9 expression and drive chemotactic invasion. Interestingly, hMSCs have been observed to transport Let-7f by exosome secretion to inhibit the growth and motility of breast cancer; such events can be reversed with the Let-7f inhibitor [104].

Several studies have found that Let-7 mediates glucose metabolism through the regulation of mammalian target of rapamycin (mTOR) [67,68,76,89]. It is also a well-known negative regulator of autophagy. Notably, human growth hormone receptors (GHR) have played an essential role in glucose metabolism and are linked to mTOR activity. A murine model revealed that, under limited nutrients, growth hormone maintained the cellular glucose level through gluconeogenesis, accompanied by the induction of autophagy [105]. In addition, GHR has been identified to contribute to breast and prostate cancer malignancy [106,107]. Elzein et al. reported that GHR is the target of miR-202. Increased miR-202 suppresses the expression of GHR in MCF and LNCaP cells [108]. Additionally, it has been reported that PKM2 and mTOR expression is downregulated under glucose restriction in breast cancer, which reverses the Warburg effect of cells [109]. Strikingly, these molecules were all be Let-7 downstream effectors. Such regulation may explain how Let-7 mediates autophagy and glucose metabolism to regulate cancer cell progression (Figure 1).

4. Conclusions