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Research article Special Issues

Identification of driver genes with aberrantly alternative splicing events in pediatric patients with retinoblastoma

  • Received: 13 September 2020 Accepted: 28 October 2020 Published: 01 December 2020
  • Retinoblastoma (RB) is one of the most common cancer in children. However, the specific mechanism about RB tumorigenesis has not been fully understood. In this study, to comprehensively characterize the splicing alterations in the tumorigenesis of RB, we analyzed the differential alternative splicing events in RB. Specifically, the isoforms of RB1 were downregulated in the RB samples, and a large proportion of differentially expressed genes had multiple differentially expressed transcripts (64%). We identified 1453 genes with differential alternative splicing, among which, SE accounted for the majority, followed by MXE, RI, A3SS, and A5SS. Furthermore, the biological function related to the normal function of eyes, and E2F family TFs were significantly enriched by the genes with differential alternative splicing. Among the genes associated with visual sense, ABCA4 was found to have two mutually exclusive exons, resulting in two isoforms with different functionalities. Notably, DAZAP1 was identified as one of the critical splicing factors in RB, which was potentially involved in E2F and RB pathways. Functionally, differential binding sites in DAZAP1 protein were significantly observed between RB and normal samples. Based on the comprehensive analysis of the differential alternative splicing events and splicing factors, we identified some driver genes with differential alternative splicing and critical splicing factors involved in RB, which would greatly improve our understanding of the alternative splicing process in the tumorigenesis of RB.

    Citation: Zhenlei Yang, Jie Wang, Ruixi Zhu. Identification of driver genes with aberrantly alternative splicing events in pediatric patients with retinoblastoma[J]. Mathematical Biosciences and Engineering, 2021, 18(1): 328-338. doi: 10.3934/mbe.2021017

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  • Retinoblastoma (RB) is one of the most common cancer in children. However, the specific mechanism about RB tumorigenesis has not been fully understood. In this study, to comprehensively characterize the splicing alterations in the tumorigenesis of RB, we analyzed the differential alternative splicing events in RB. Specifically, the isoforms of RB1 were downregulated in the RB samples, and a large proportion of differentially expressed genes had multiple differentially expressed transcripts (64%). We identified 1453 genes with differential alternative splicing, among which, SE accounted for the majority, followed by MXE, RI, A3SS, and A5SS. Furthermore, the biological function related to the normal function of eyes, and E2F family TFs were significantly enriched by the genes with differential alternative splicing. Among the genes associated with visual sense, ABCA4 was found to have two mutually exclusive exons, resulting in two isoforms with different functionalities. Notably, DAZAP1 was identified as one of the critical splicing factors in RB, which was potentially involved in E2F and RB pathways. Functionally, differential binding sites in DAZAP1 protein were significantly observed between RB and normal samples. Based on the comprehensive analysis of the differential alternative splicing events and splicing factors, we identified some driver genes with differential alternative splicing and critical splicing factors involved in RB, which would greatly improve our understanding of the alternative splicing process in the tumorigenesis of RB.


    Right (resp., left, null) quasi-Frobenius extensions of rings were first introduced by Müller [1] as a generalization of quasi-Frobenius rings and Frobenius extensions. They are closely related with separable extensions and group rings [1,2]. For instance, K. Hirata [2] established that a central projective separable extension equivalently characterized as a quasi-Frobenius extension. Extensive research has focused on the invariant properties of rings under right (resp., null) quasi-Frobenius extensions. Notably, key homological invariants such as the dominant dimension, injectivity, and related properties are preserved under quasi-Frobenius extensions, as demonstrated in [1,3].

    In the 1960s, Auslander and Bridge [4] initially introduced the concept of finitely generated modules having Gorenstein dimension zero over a Noetherian ring; these modules are now widely termed Gorenstein projective (see [4,5] for further details). A number of studies, including [6,7,8,9,10], have explored the invariance of Gorenstein projective modules under various ring extensions such as excellent extensions, Frobenius extensions, trivial ring extensions, and separable equivalences.

    It is known that the Gorenstein algebra, the Cohen-Macaulay finite algebra (CM-finite algebra, for short), and the Cohen-Macaulay finite algebra (CM-free algebra, for short) are characterized in terms of Gorenstein projective modules [3,11]. Recall that a ring Λ is called a Gorenstein ring, if the injective dimension of ΛΛ and that of ΛΛ are finite. Let ΓΛ be a quasi-Frobenius extension of Λ with ΓΛ a generator for Λ-modules. It follows from [3, Proposition 7] that Λ is a Gorenstein ring when Γ is so. Note that a generator for Λ-modules is completely faithful, but a completely faithful module is not a generator in general (see [12, P234], for detail). In this study, we shall develop their arguments and apply obtained results to right quasi-Frobenius extensions ultimately establishing the following theorem.

    Theorem A. Let Γ be a right quasi-Frobenius extension of a two-sided Noetherian ring Λ.

    (1) Suppose that Γ is a completely faithful left Λ-module. Then, Λ is a Gorenstein ring, when Γ is so.

    (2) Suppose that Γ is a separable extension of Λ. Then, Γ is a Gorenstein ring, when Λ is so.

    In [10], Zhao proved that CM-free (resp., CM-finite) properties are invariant under separable Frobenius extensions of commutative Artin rings. It is shown by Huang et al. [7] that CM-free (resp., CM-finite) properties are invariant under the strongly separable quasi-Frobenius extensions. In this paper, we shall improve them and prove the same results for right quasi-Frobenius extensions of Artin algebras.

    Theorem B. Let Γ be a separable right quasi-Frobenius extension of an Artin algebra Λ.

    (1) If Λ is CM-free, then so is Γ. Furthermore, if Γ is a generator for Λ-modules, the converse also holds.

    (2) If Λ is CM-finite, then so is Γ. Furthermore, if M is a relative generator for FG(Γ), where FG(Γ) is the category formed by all finitely generated Gorenstein projective left Λ-modules, then EndΛM is a right quasi-Frobenius extension of EndΓM.

    Essential definitions and results frequently employed in this work are given in Section 2. Theorems A and B are proved in Section 3.

    In this study, unless otherwise specified, all rings are assumed to be two-sided Noetherian rings, and all modules are finitely generated left modules. Given a ring Λ, the category composed of all finitely generated left Λ-modules is denoted by modΛ.

    Definition 2.1. ([1, Definition 1.1]) Let Λ be a subring of Γ containing the identity of Γ. Then Γ is said to be a ring extension of Λ, represented as ΓΛ. Such an extension ΓΛ is said to be a right quasi-Frobenius extension (right QF-extension, for short), if

    (1) ΓΛ is projective;

    (2) ΛΓΓaddΛ(HomΛ(ΓΓΛ,ΛΛΛ)Γ, where addΛ(HomΛ(ΓΓΛ,ΛΛΛ)Γ denotes the category formed by direct summands of finite copies of ΛHomΛ(ΓΓΛ,ΛΛΛ)Γ.

    The definition of a left quasi-Frobenius extension follows analogously. When a right QF-extension ΓΛ additionally satisfies the criteria for a left QF-extension, it is termed a quasi-Frobenius extension (QF-extension, for short). Moreover, a QF-extension ΓΛ is called a Frobenius extension if there is a bimodule isomorphism ΛΓΓΛHomΛ(ΓΓΛ,ΛΛΛ)Γ; see [13, Theorem 1.2] for detail.

    The following remark is easy, which is important for our arguments.

    Remark 2.2. Let ΓΛ be a right QF-extension, then

    (1) ΓHomΛ(ΛΓΓ,ΛΛ)ΛaddΓΓΛ.

    (2) ΛΓ is projective.

    Recall from [13, Section 2.4] that a ring extension ΓΛ is said to be a separable extension, if the map

    π:ΓΛΓΓviaπ(ab)=ab

    is a split epimorphism of the Γ-bimodule. By the definition of separable extensions, we have the following lemma.

    Lemma 2.3. Let ΓΛ be a separable extension and NmodΓ. Then, we have ΓNaddΓ(ΓΛN).

    Proof. By the definition of separable extensions, there exist a Γ-bimodule Y and a Γ-bimodule isomorphism ΓΓΓΓYΓΓ(ΓΛΓ)Γ. Then, for a Γ-module N, one gets Γ-module isomorphisms

    ΓΓΛNΓ(ΓΛΓ)ΓNΓ(ΓY)ΓNΓNΓ(YΓN).

    Thus, we have ΓNaddΓ(ΓΛN).

    For a module MmodΛ with the projective presentation,

    P1fP0M0.

    Following [4], the transpose of M, denoted by TrM, is defined as the cokernel of the dualized map of f, where ()=HomΛ(,Λ).

    Lemma 2.4. ([6, Lemma 3.1]) Suppose that ΓΛ is a ring extension.

    (1) For any MmodΛ, there exist projective right Γ-modules Q1,Q2 and a right Γ-module isomorphism Tr(ΓΛM)ΓQ1(TrMΛΓ)ΓQ2.

    (2) If ΓΛ is projective and NmodΓ, then there exist projective right Λ-modules P1,P2 and a right Λ-module isomorphism (TrN)ΛP1TrNΓHomΛ(ΛΓΓ,ΛΛ)ΛP2.

    Recall from [4, Proposition 3.8] that M is said to have Gorenstein dimension zero, denoted by GpdΛM=0, if Ext1Λ(ΛM,Λ)=0=Ext1Λo((TrM)Λ,Λ). These modules are now often termed Gorenstein projective (see [5, Definition 10.2.1] for detail). The full subcategory of modΛ comprising all finitely generated Gorenstein projective modules is denoted by FG(Λ). The Gorenstein projective dimension (or Gorenstein dimension) of M, denoted by GpdΛM, is defined as the minimal integer n1 for which there exists an exact sequence in modΛ: 0DnD1D0M0 with each DiFG(Λ) (see [4,14] for detail). If no such finite sequence exists, GpdΛM is defined to be infinite. The finitistic dimension of Λ, denoted fin.dimΛ, is defined as the supremum of projective dimensions across all modules M in modΛ having finite projective dimensions.

    Lemma 2.5. [6, Lemma 2.5] For a two-sided Noetherian ring Λ, fin.dimΛ=sup{GpdMMmodΛ and GpdM<}.

    Let B be a Λ-module. From [15, P87], we know that its character module B+ is the right Λ-module HomZ(B,Q/Z). Recall from [12, P233] that B is called completely faithful, provided that for every homomorphism f, fΛB=0 implies f=0. Recall that B is a generator (resp., cogenerator) for Λ-modules if each Λ-module is a quotient (resp., submodule) of direct sums (resp., products) of B. Clearly, every generator is completely faithful, but the converse is not true in general.

    Lemma 2.6. ([12, P234]) The equivalence of the following statements holds for a projective Λ-module Q.

    (1) Q is a completely faithful module.

    (2) Let V be a right Λ-module. Then, VΛQ=0 implies V=0,

    (3) The character module Q+ is a cogenerator in modΛop.

    Lemma 2.7. Let Λ and Γ be Noetherian rings.

    (1) [15, Corollary 10.65] In the situation (ΛA,ΓBΛ,ΓC), assume that BΛ is projective. Then, for any n1, there is an isomorphism

    ExtnΓ(BΛA,C)ExtnΛ(A,HomΓ(B,C)).

    (2) [5, Theorem 3.2.15] In the situation (ΛA,ΓBΛ,ΓC), assume that ΛA is projective. Then, for any n1, there is an isomorphism

    ExtnΓ(C,BΛA)ExtnΓ(C,B)ΛA.

    Lemma 3.1. Let ΓΛ be a right QF-extension, and XmodΛ. Then, for any i1, we have the following isomorphisms

    (1) ExtiΓ(ΓΛX,Γ)ExtiΛ(X,Λ)ΛΓ;

    (2) ExtiΓ(ΓΛX,Γ)ExtiΛ(ΛX,ΛΓ).

    Proof. Noting that ΛΓ and ΓΛ are projective by assumption and by Remark 2.2(2), the assertion follows directly from Lemma 2.7.

    Lemma 3.2. Suppose that ΓΛ is a right QF-extension with ΛΓ completely faithful. Then,

    (1) HomΛ(ΛΓ,ΛΛΛ) is a completely faithful right Λ-module.

    (2) ΓΛ is completely faithful.

    Proof. (1) It suffices to prove that the character module HomΛ(ΛΓ,ΛΛΛ)+Λ is a cogenerator by Lemma 2.6(3), because HomΛ(ΛΓ,ΛΛΛ)Λ is projective by Remark 2.2(1).

    Let X be a finitely generated right Λ-module satisfying HomΛ(X,HomΛ(ΛΓΓ,ΛΛΛ)+)=0. Since ΛΓ is projective, by [14, P78,Theorem 3.2.11], there are isomorphisms

    0=HomΛ(XΛ,HomΛ(ΛΓΓ,Λ)+Λ)HomΛ(XΛ,Λ+ΛΓ)HomΛ(XΛ,Λ+)ΛΓ,

    So, HomΛ(ΛX,Λ+)=0 by the completely faithful property of ΛΓ. Since Λ+ is also a cogenerator, X=0, which implies that HomΛ(ΛΓ,ΛΛ)+ is a cogenerator. Thus, we obtain our claim by Lemma 2.6(3).

    (2) Since HomΛ(ΛΓΓ,Λ)ΛaddΓΛ by Remark 2.2(1), Γ is a completely faithful right Λ-module as desired.

    Remark 3.3. (1) Let ΓΛ be a right QF-extension such that Γ is a completely faithful right Λ-module. It is not known that Γ is completely faithful as a left Λ-module.

    (2) Let ΓΛ be a right QF-extension with ΛΓ a generator for Λ-modules, then ΓΛ is completely faithful by Lemma 3.2. For example, if Γ is an excellent extension of Λ. It follows from [6, Proposition 4.3] that Γ is a right QF-extension of Λ. By the definition of excellent extensions, Γ is a free Λ-module. It follows from Lemma 3.2 that Γ is a completely faithful right Λ-module.

    Proposition 3.4. Let ΓΛ be a right QF-extension, and let MmodΛ. If ΛM is Gorenstein projective, so is Γ(ΓΛM). Furthermore, if ΛΓ is a completely faithful Λ-module, then the converse holds.

    Proof. By assumption, for any i1, we have ExtiΛ(M,Λ)=0=ExtiΛ((TrM)Λ,Λ). Since ΓΛ is a right QF-extension, one obtains that ΛΓ is projective by Remark 2.2(2). By Lemma 3.1(1), one has ExtiΓ(ΓΛM,Γ)ExtiΛ(M,Λ)ΛΓ=0 for any i1. On the other hand, since both ΛΓ and ΓΛ are projective, by Lemma 2.4 and Lemma 3.1(2), for any i1, there are isomorphisms

    ExtiΓ(Tr(ΓΛM)Γ,Γ)ExtiΓ((TrM)ΛΓ,Γ)ExtiΛ(TrM,Γ)=0.

    This implies that ΓΛMFG(Γ).

    Conversely, assume that ΛΓ is completely faithful and ΓΛMFG(Γ). Then, ExtiΓ(ΓΛM,Γ)=0=ExtiΓ(Tr(ΓΛM),Γ) for any i1.

    By Lemma 3.1(1), one gets 0=ExtiΓ(ΓΛM,Γ)ExtiΛ(M,Λ)ΛΓ for any i1. Since ΛΓ is completely faithful, by Lemma 2.6(2), ExtiΛ(M,Λ)=0 for each i1.

    It remains to show Ext1Λ(TrM,Λ)=0. Since ΛΓ is projective by Remark 2.2(2), for i1, we have

    0=ExtiΓ(Tr(ΓΛM),ΓΓ)ExtiΓ(TrMΛΓ,ΓΓ) (by Lemma 2.4)ExtiΛ((TrM)Λ,ΓΛ)ExtiΛ((TrM)Λ,ΓΛΛ)ΓΛExtiΛ(TrM,Λ). (by Lemma 2.7(2))

    Note that Γ is a completely faithful right Λ-module by Lemma 3.2(2), then Ext1Λ((TrM)Λ,ΛΛ) = 0.

    Corollary 3.5. Let ΓΛ be a right QF-extension with ΛΓ completely faithful, and let MmodΛ. Then

    GpdΓ(ΓΛM)=GpdΛM.

    Proof. Since ΓΛ is projective, by [6, Proposition 3.2], one obtains GpdΓ(ΓΛM)GpdΛM.

    On the other hand, without loss of generality, let GpdΓ(ΓΛM)=n<. Taking an exact sequence in modΛ,

    0KnGn1G1G0M0

    with each GiFG(Λ). Applying the exact functor ΓΛ to the above sequence yields an exact sequence in modΓ

    0ΓΛKnΓΛGn1ΓΛG1ΓΛG0ΓΛM0.

    By the first part of Proposition 3.4, one gets ΓΛGiFG(Γ) for all 0in1. So, ΓΛKnFG(Γ) by assumption and by [16, Theorem 2.20]. It follows from the second part of Proposition 3.4 that KnFG(Λ). This implies GpdΛMn by [16, Corollary 2.21].

    Corollary 3.6. Suppose that ΓΛ is a right QF-extension of Λ and MmodΛ. If M is Gorenstein projective as a Λ-module, then so is HomΛ(ΛΓΓ,M) as a Γ-module.

    Proof. Since ΓΛ is a right QF-extension, from Remark 2.2 one has HomΛ(ΛΓΓ,M)HomΛ(ΛΓΓ,Λ)ΛM addΓ(ΓΛM). By Proposition 3.4, ΓΛM is Gorenstein projective. The assertion follows from [16, Theorem 2.5].

    Proposition 3.7. Let Γ be a right QF-extension of Λ and NmodΓ. Suppose that N is Gorenstein projective as a Γ-module, then so is the underlying module N as a Λ-module. Furthermore, the converse holds when ΓΛ is separable.

    Proof. By assumption, for any i1, one has ExtiΓ(N,Γ)=0=ExtiΓ((TrN)Γ,Γ). Hence, for each i1, ExtiΓ(ΓN,HomΛ(ΛΓΓ, Λ))=0, because ΓHomΛ(ΛΓΓ,Λ) is projective by Remark 2.2(1). By Lemma 2.7(1), for any positive integer i, we have

    ExtiΛ(ΛN,Λ)ExtiΛ(ΛΓΓN,Λ)ExtiΓ(ΓN,HomΛ(ΛΓΓ,ΛΛ))=0.

    On the other hand, since ΛΓ is projective by Remark 2.2(2), for any positive integer i, we have

        ExtiΛ((TrN)Λ,Λ)ExtiΛ(TrΓNΓHomΛ(ΛΓΓ,ΛΛ),Λ) (by Lemma 2.4)ExtiΓ(TrΓN,HomΛ(HomΛ(ΛΓΓ,ΛΛ),Λ)) (by Lemma 2.7(1))ExtiΓ((TrN)Γ,Γ)=0.

    This means ΛNFG(Λ) as desired.

    Conversely, assume that NFG(Λ). By the first part of Proposition 3.4, ΓΛNFG(Γ). Noting that ΓΛ is separable, then, by Lemma 2.3, we obtain ΓNaddΓ(ΓΛN). Thus, by [16, Theorem 2.5], one gets NFG(Γ).

    Proposition 3.8. Let ΓΛ be a right QF-extension, and let NmodΓ. Then, GpdΛNGpdΓN. Moreover, the equality holds true when ΓΛ is separable.

    Proof. We may assume, without loss of generality, that GpdΓN=m, then we have the following exact sequence in modΓ:

    0DmDm1D0N0

    in modΓ, where each ΓDi lies in FG(Γ). Clearly, the above sequence remains exact in modΛ. Also, by the first part of Proposition 3.7, we have ΛDiFG(Λ), for each 0im. This implies GpdΛNm.

    Let ΓΛ be a separable right QF-extension, and we have ΓNaddΓ(ΓΛN), by Lemma 2.3. So, one has GpdΓNGpdΓ(ΓΛN)GpdΛN by ([6, Proposition 3.2].

    Theorem 3.9. If ΓΛ is a separable right QF-extension with ΛΓ completely faithful, then

    fin.dimΓ=fin.dimΛ.

    Proof. This assertion follows immediately from Lemma 2.5, Corollary 3.5, and the second part of Proposition 3.8.

    Theorem 3.10. Let Γ and Λ be two Artin algebras.

    (1) Let ΓΛ be a right QF-extension with ΛΓ completely faithful. If Γ is Gorenstein, then so is Λ.

    (2) Let ΓΛ be a separable right QF-extension. If Λ is Gorenstein, then so is Γ.

    Proof. According to [17, Theorem 1.1], an Artin algebra is Gorenstein precisely when every finitely generated left module has finite Gorenstein projective dimension. (1) follows directly from Corollary 3.5, while (2) is an immediate consequence of the first part of Proposition 3.8.

    Let Λ be an Artin algebra over a commutative Artin ring R. Recall from [18, Section 1] that a Λ-module M is termed semi-Gorenstein projective, provided Ext1Λ(M,Λ)=0. We write Λ={XmodΛ|Ext1Λ(X,Λ)=0}. Λ is termed left weakly Gorenstein, if GP(Λ)=Λ. The notion of left weakly Gorenstein algebras is a generalization of that of Gorenstein algebras. Hence, Λ is left weakly Gorenstein if, and only if, every semi-Gorenstein projective Λ-module is Gorenstein projective.

    Theorem 3.11. Let Γ and Λ be two Artin R-algebras.

    (1) Let ΓΛ be a right QF-extension with ΛΓ completely faithful. If Γ is left weakly Gorenstein, then so is Λ.

    (2) Let ΓΛ be a separable right QF-extension. If Λ is left weakly Gorenstein, then so is Γ.

    Proof. (1) Let M be a semi-Gorenstein projective Λ-module. Then, one has Ext1Λ(M,Λ)=0. By assumption and by Remark 2.2(2), both ΛΓ and ΓΛ are projective. Then, by Lemma 2.7(1), for any i1, we have ExtiΓ(ΓΛM,Γ)ExtiΛ(M,Γ)=0, which implies that ΓΛM is semi-Gorenstein projective. So, ΓΛMFG(Γ) by assumption. It follows from the second part of Proposition 3.4 that MFG(Λ). Hence, Λ is a left weakly Gorenstein algebra.

    (2) suppose that Λ is left weakly Gorenstein. Given a semi-Gorenstein Γ-module N, by Lemma 2.7(1) and by [6, Proposition 3.2], there are isomorphisms ExtiΛ(N,Λ)ExtiΛ(ΓΓN,Λ)ExtiΓ(ΓN,HomΛ(ΛΓΓ,Λ)) = 0 for any i1, because ΓHomΛ(ΛΓΓ, Λ) is projective by Remark 2.2(1). It implies that N is also a semi-Gorenstein Λ-module, and, hence, one obtains NFG(Λ) by assumption. Therefore, NFG(Γ) by the second part of Proposition 3.7. Thus, we complete this proof.

    The following lemma is due to Y. Kitamura in [19].

    Lemma 3.12. [19, Theorem 1.2] Let ΓΛ be a right QF-extension and NmodΓ. If ΓΓΛNaddΓN, then EndΛNEndΓN also is a right QF-extension.

    Let Λ be an Artin R-algebra. By D(), we denote the standard duality HomR(,E(R/rad(R))), where E(R/rad(R)) is the injective envelope of R/rad(R). Following [11, Section 1], Λ is termed Cohen-Macaulay free, or simply, CM-free, provided FG(Λ)=P(Λ) (where P(Λ) is the category of finitely generated projective Λ-modules). Additionally, Λ is called Cohen-Macaulay finite[20, Section 8], or simply, CM-finite, if there exists a Gorenstein projective Λ-module G such that FG(Λ)=addΛG, and G is called a relative generator for FG(Λ). Clearly, a Cohen-Macaulay free algebra is Cohen-Macaulay finite.

    Theorem 3.13. Suppose Γ is a separable right QF-extension of an Artin R-algebra Λ. Then,

    Λ is CM free generator Γ is CM freeΛ is CM finiteΓ is CM finite.

    That is,

    (1) If Λ is CM-free, then so is Γ. Moreover, the converse holds when Γ is a generator for modΛ.

    (2) If Λ is CM-finite, then so is Γ. Moreover, if M is a relative generator for FG(Γ), then the ring homomorphism ρ:EndΓMEndΛM is a right QF-extension.

    Proof. (1) For NFG(Γ), one has NFG(Λ) by the first part of Proposition 3.7. Hence, by assumption, one obtains ΛNP(Λ). So, ΓΛNP(Γ). Noting that ΓΛ is separable, ΓNaddΓ(ΓΛN) by Lemma 2.3. Then, ΓN is projective. Thus, Γ is a CM-free algebra.

    Conversely, assume that ΛΓ is a generator, and Γ is CM-free. Let MFG(Λ). By Corollary 3.6, we have HomΛ(ΛΓΓ,M)FG(Γ), which is projective by assumption. Hence, D(HomΛ(ΛΓΓ,M)) is an injective right Γ-module. By [15, Lemma 3.60], there is an isomorphism D(HomΛ(ΛΓΓ,M))DMΛΓ. Hence, DM is injective by [3, Proposition 7], which implies that M is projective. Therefore, Λ is CM-free.

    (2) Assume that Λ is Cohen-Macaulay finite, with G being a relative generator for FG(Λ). By Proposition 3.4, we have ΓΛGFG(Γ). For any XFG(Γ), one gets ΛXFG(Λ) by Proposition 3.7. So, ΛXaddΛG and, hence, one gets Γ(ΓΛX)addΓ(ΓΛG). On the other hand, noting that the ring extension ΓΛ is separable, we have ΓXaddΓ(ΓΛX). It follows that ΓXaddΓ(ΓΛG), which means that Γ is CM-finite.

    By assumption and by the above discussion, one obtains that Γ is Cohen-Maulay finite. If M is a relative generator for FG(Γ), then we have that MFG(Λ) by Proposition 3.7. It follows from the first part of Proposition 3.4 that Γ(ΓΛM)FG(Γ). So, Γ(ΓΛM)addΓM by assumption and by Proposition 3.4, which satisfies the condition of Lemma 3.12. Therefore, EndΛMEndΓM is a right QF-extension as a direct consequence of Lemma 3.12.

    Recall that a separable extension ΓΛ is said to be strongly separable, if MaddΛ(ΓΛM) for any Λ-module M. Under this condition, ΛΓ is a generator for Λ-modules. Due to Theorems 3.10 and 3.13, we re-obtain results in [7].

    Corollary 3.14. Let Γ be a strongly separable quasi-Frobenius extension of Λ. Then

    (1) ([7, Corollary 3.9]) Λ is Gorenstein if, and only if, Γ is Gorenstein.

    (2) ([7, Corollary 3.10]) Λ is CM-free if, and only if, Γ is CM-free.

    The authors declare they have not used Artificial Intelligence (AI) tools in the creation of this article.

    This work was financially supported by NSFC 12061026 and Foundation for University Key Teacher by Henan Province 2019GGJS204.

    The authors declare there are no conflicts of interest.



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